With the recent US approval of the IL-5-directed monoclonal antibody (mAb) mepolizumab as an add-on therapy for patients with COPD, the era of COPD biologics is undeniably here.
Mepolizumab is the second approved biologic for the prevention of COPD exacerbations. Dupilumab, an IL-4- and IL-13-targeted mAb approved in 2024, was the first biologic to be included in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report, recommended for treating patients with chronic bronchitis exacerbations despite triple therapy and blood eosinophil counts (BECs) ≥ 300 cells/μL.
Gerard J. Criner, MD, FCCP, Chair and Professor of Thoracic Medicine and Surgery at the Lewis Katz School of Medicine at Temple University and Director of the Temple Lung Center, said, “For a chronic disease that is associated with high morbidity and mortality and is, globally, the third leading cause of death, and, in the United States, the sixth leading cause of death, we are making incremental progress. COPD has long been considered difficult to treat. During the past decade, the progress in COPD treatments has accelerated, and I hope these advances continue.”
Two biologics now approved
The approval of dupilumab was based on data from replicate pivotal phase 3 studies, BOREAS and NOTUS. These studies compared dupilumab with placebo in adults who actively smoke or previously smoked with a history of moderate to severe COPD exacerbations and a BEC ≥ 300 cells/μL.1
Adding dupilumab to standard triple therapy reduced moderate to severe exacerbations (by 30% in BOREAS and 34% in NOTUS), improved lung function, and increased the St. George’s Respiratory questionnaire (SGRQ) score.1
Mepolizumab was approved based on MATINEE study findings and building on previous studies.2,3 In MATINEE, add-on mepolizumab therapy reduced exacerbations by 21%, prolonged time to first moderate or severe exacerbation, and reduced the rate of emergency department visits, hospitalization, or both due to exacerbations by 35% in patients with COPD with a history of exacerbations and BECs ≥ 300 cells/μL (at screening) or ≥ 150 cells/µL (in the preceding 12 months or two to three weeks before randomization). There were no significant differences in SGRQ scores between mepolizumab and placebo.2 One-third of the patients smoked actively.
“MATINEE differed from BOREAS and NOTUS in that it included an expanded population of patients—those with more severe airway inflammation, [those with] very severe airway obstruction, and those with and without chronic bronchitis. MATINEE also used exhaustive exclusion criteria,” Dr. Criner said.
“The study really focused on patients with COPD with a type 2 inflammation/eosinophilic phenotype. About a third of the patients in MATINEE also had either physician-diagnosed or self-awareness of emphysema,” he added. “The outcomes showed that mepolizumab benefited a wider spectrum of patients with COPD in terms of the airflow obstruction severity over a longer period, as MATINEE was extended because of the COVID-19 pandemic.”
More biologics wait in the wings
The recent approvals of biologics represent a successful course correction based on lessons from early failures when biologics were assessed in broad COPD cohorts with less stringent BEC cutoffs, said Sanjay Ramakrishnan, MBBS, PhD, FRACP, Senior Lecturer at the University of Western Australia.
“It comes down to finding the right patient,” Dr. Ramakrishnan said. “In COPD, it seems to be patients with elevated BECs within the past 12 months and a history of exacerbations who benefit from biologic therapy.”
Other biologics are advancing along the clinical development pipeline.
In the COURSE phase 2a trial, tezepelumab, an mAb targeting thymic stromal lymphopoietin, reduced moderate or severe exacerbations in patients with COPD with BECs ≥ 150 cells/µL, with greater benefit seen in patients with BECs ≥ 300 cells/µL.4 Two registrational phase 3 studies, JOURNEY and EMBARK, are currently evaluating tezepelumab in people with COPD with BECs ≥ 150 cells/µL.5,6
In addition to COURSE data, Dr. Criner also pointed out top-line results from the AERIFY-1 study of itepekimab, which met the primary end point of a statistically significant reduction in moderate or severe exacerbations in patients who had formerly smoked, regardless of eosinophilic phenotype, and provided a clinically meaningful benefit.7
Itepekimab, an IL-33-directed mAb, reduced moderate or severe acute exacerbations by 27% compared with placebo after 52 weeks in AERIFY-1.7 However, itepekimab did not decrease exacerbations after 52 weeks in AERIFY-2, despite showing benefit earlier in the study. Notably, both trials included similar populations of patients with a history of smoking and moderate to severe COPD who were aged 40 to 85 years, regardless of BECs.7
“While AERIFY-1 was positive, AERIFY-2 was negative. These data make it unlikely that this agent will be licensed in a broad population,” Dr. Ramakrishnan said. The reasons for the negative results in AERIFY-2 are currently unclear.
When it comes to the acute management of exacerbations, promising efficacy has also been reported for benralizumab, a humanized mAb against IL-5 receptor-α. In the phase 2 ABRA study, benralizumab reduced treatment failure to 45% from 75% with prednisolone in patients with acute exacerbations of asthma or COPD.8 Benralizumab is being evaluated in patients with moderate to extremely severe COPD with a history of frequent COPD exacerbations and BECs ≥ 300 cells/μL in the phase 3 RESOLUTE study.9
Notably, the COPD-HELP trial tested the use of mepolizumab for severe exacerbations of eosinophilic COPD in the acute setting and it was not effective.10
Speaking of the different mAbs and targets in the context of COPD pathophysiology, Dr. Ramakrishnan said, “COPD pathophysiology is mixed and complex, and there are many reasons why people develop COPD and many exacerbation triggers. These epithelial and other interleukins are a small part of the underlying pathophysiology. Our hope is that by targeting this aspect, we can make headway in improving COPD exacerbations. In patients with higher BECs, who need to be identified efficiently, the biologics that target eosinophilic inflammation are improving outcomes.”
BECs: A moving target?
BECs are a marker of pulmonary type 2 inflammation, mediated by Th2 cells and eosinophils, which significantly contribute to COPD exacerbations in some patients.
Dr. Ramakrishnan said that BEC not only predicts drug response but also identifies patients with COPD at risk of future exacerbations. However, BEC is a labile marker, he said, and there are data suggesting that it is important to measure BEC more than once.
Recent research led by Lydia J. Finney, MBBCh, PhD, Clinical Associate Professor in Respiratory Medicine at the National Heart and Lung Institute, Imperial College London, showed that repeated, rather than a single, BEC assessment may better predict risk of future exacerbations.11
Dr. Finney explained that in their cohort of 100 patients with COPD, BECs fluctuated throughout a four-year follow-up.
“While 300 cells/µL has been identified as a BEC threshold for biologic efficacy in many clinical trials, in our study, 18% had a persistently high BEC (≥ 300 cells/µL),” Dr. Finney said. “About half of the patients always had a persistently low BEC (< 300 cells/µL), and BECs were intermittently high in about 30% of patients. Most patients (90%) with persistently high BECs had high BECs at exacerbation. However, high BECs were also detected in about 50% of patients in the intermittently high [BEC] or 25% of patients in the persistently low BEC groups.”
Dr. Ramakrishnan said the context of BEC measurement matters.
“Measuring BECs in patients who are stable may miss patients who may benefit from biologic therapy, as only about a third of patients have elevated BECs in this setting,” he said.
Dr. Ramakrishnan added that BECs measured at exacerbation in patients receiving prednisolone may be artificially suppressed, as prednisolone (and other corticosteroids) lowers BECs.
The GOLD Report includes recommendations for BEC assessment to guide use of inhaled steroids and dupilumab; however, it does not specify timing or context for BEC testing.
“Current COPD guidelines recommend BEC assessment, so it should become a routine part of care. But moving from single or sporadic BEC measurements to measuring BECs at exacerbations is a huge step, another paradigm shift, especially in primary care where most exacerbations are first reported/managed,” Dr. Ramakrishnan said.
Dr. Ramakrishnan and colleagues showed that it is feasible to measure BEC in primary care at acute COPD exacerbation to guide prednisolone use in the STARR2 trial.12 In the ABRA trial, elevated BECs at exacerbation identified patients who achieved greater responses with benralizumab, Dr. Ramakrishnan said.8
Dr. Ramakrishnan noted, “While guidelines currently include recommendations on BEC testing, what remains is how to change physician practice.”
“The key message is that you cannot rely on just one blood test,” Dr. Finney said. “While it may be challenging to evaluate BECs at multiple instances in real-world clinical practice, conducting BEC assessments at exacerbation might be a clue to identify potential candidates for biologic therapy.”
Tackling unmet needs
“In COPD, the main goal of biologic therapy is to reduce exacerbations, and any concomitant improvements in lung function are an add-on benefit, if they occur,” Dr. Ramakrishnan said. COPD exacerbations are a significant health care resource and economic burden. Globally, COPD-related exacerbations are estimated to increase by nearly 25%, with a nearly sevenfold increase in health care costs.13
“Although the positive findings from studies of biologics, including dupilumab and mepolizumab, are great news, the benefit thus far has been limited to a small proportion of patients with COPD—the 20% to 40% who have type 2 inflammation with an eosinophilic phenotype,” Dr. Criner said. “There is an unmet need for new therapies for patients who experience an exacerbation but do not have high BECs.”
While a substantial proportion of people with COPD and exacerbations do not have an eosinophilic endotype, this proportion may not be as high as previously thought, as suggested by Dr. Finney’s work.
Nevertheless, biomarkers and effective targeted therapies for patients with noneosinophil-driven exacerbations are needed.
“One of the good things about COPD biologics is that now people are thinking about the different reasons and categories of exacerbation, rather than grouping all exacerbations together,” Dr. Ramakrishnan said. “To prevent exacerbations in patients with low or no elevation in BECs, it is necessary to identify the underlying driver(s) of exacerbation.”
This article was originally published in the Fall 2025 issue of CHEST Physician.
References
1. Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N Engl J Med. 2023;389(3):205-214. doi:10.1056/NEJMoa2303951
2. Sciurba FC, Criner GJ, Christenson SA, et al. Mepolizumab to prevent exacerbations of COPD with an eosinophilic phenotype. N Engl J Med. 2025;392(17):1710-1720. doi:10.1056/NEJMoa2413181
3. Pavord ID, Chapman KR, Bafadhel M, et al. Mepolizumab for eosinophil-associated COPD: analysis of METREX and METREO. Int J Chron Obstruct Pulmon Dis. 2021 Jun 16;16:1755-1770. doi: 10.2147/COPD.S294333. PMID: 34163157; PMCID: PMC8215850.
4. Singh D, Brightling CE, Rabe KF, et al. Efficacy and safety of tezepelumab versus placebo in adults with moderate to very severe chronic obstructive pulmonary disease (COURSE): a randomised, placebo-controlled, phase 2a trial. Lancet Respir Med. 2025;13(1):47-58. doi:10.1016/S2213-2600(24)00324-2
5. A Study to Investigate the Efficacy and Safety of Tezepelumab in Adult Participants With Moderate to Very Severe COPD (D5241C00007) (JOURNEY). ClinicalTrials.gov identifier: NCT06878261. Updated June 26, 2025. https://clinicaltrials.gov/study/NCT06878261?locStr=Peru&country=Peru&rank=10
6. A Study to Investigate the Efficacy and Safety of Tezepelumab in Adult Participants With Moderate to Very Severe COPD (EMBARK). ClinicalTrials.gov identifier: NCT06883305. Updated June 26, 2025. https://clinicaltrials.gov/study/NCT06883305
7. Rabe KF, Martinez FJ, Bhatt SP, et al. AERIFY-1/2: two phase 3, randomised, controlled trials of itepekimab in former smokers with moderate-to-severe COPD. ERJ Open Res. 2024;10(5):00718-2023. doi:10.1183/23120541.00718-2023
8. Ramakrishnan S, Russell REK, Mahmood HR, et al. Treating eosinophilic exacerbations of asthma and COPD with benralizumab (ABRA): a double-blind, double-dummy, active placebo-controlled randomised trial. Lancet Respir Med. 2025;13(1):59-68. doi:10.1016/S2213-2600(24)00299-6
9. Efficacy and Safety of Benralizumab in Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) With a History of Frequent Exacerbations (RESOLUTE). ClinicalTrials.gov identifier: NCT04053634. Updated July 16, 2025. https://clinicaltrials.gov/study/NCT04053634
10. Flynn CA, McAuley HJC, Elneima O, et al. Mepolizumab for COPD with eosinophilic phenotype following hospitalization. NEJM Evid. 2025;4(6):EVIDoa2500012. doi:10.1056/EVIDoa2500012
11. Baraldi F, Bartlett-Pestle S, Allinson JP, et al. Blood eosinophil count stability in COPD and the eosinophilic exacerbator phenotype [published online ahead of print January 15, 2025]. Am J Respir Crit Care Med. doi:10.1164/rccm.202407-1287RL
12. Ramakrishnan S, Jeffers H, Langford-Wiley B, et al. Blood eosinophil-guided oral prednisolone for COPD exacerbations in primary care in the UK (STARR2): a non-inferiority, multicentre, double-blind, placebo-controlled, randomized controlled trial. Lancet Respir Med. 2024;12(1):67-77. doi:10.1016/S2213-2600(23)00298-9
13. Boers E, Allen A, Barrett M, et al. Forecasting the global economic and health burden of COPD from 2025 through 2050. Chest. In press. doi:10.1016/j.chest.2025.03.029
