COPD

COPD

COPD

Treating and Managing COPD

The primary treatment goals for chronic obstructive pulmonary disorder (COPD) are centered around controlling symptoms, improving quality of life, reducing exacerbations, and reducing COPD-related mortality. 1 These goals represent unmet needs in current COPD management.2

Nonpharmacologic interventions

Educational programs can help patients learn how to take their medication properly and use oxygen devices correctly. These programs can also teach special inhalation techniques and offer advice on preventing and dealing with acute breathing difficulties. There are numerous Nonpharmacologic interventions that can potentially reduce mortality rates among patients with COPD, including:1,3

Smoking cessation and avoiding secondhand smoke

Vaccination (eg, pertussis, pneumococcus, respiratory syncytial virus [RSV], coronavirus-2019 [COVID-19])

Physical activity

Pulmonary rehabilitation

Reducing exposure to other harmful agents, eg,: asbestos, beryllium, carbon dust, silica, chromium, fungi, avian droppings, and bacterial species

Oxygen therapy and ventilatory support

Surgical lung volume reduction

Some people with COPD lose a lot of weight over time. Their muscles become weaker, and they become less fit. For these patients, combining high-calorie supplements with regular weight management practices can help improve respiratory muscle strength, handgrip strength, weight gain, exercise performance, and quality of life.4

Nutraceuticals5

Nutraceuticals are gaining popularity as a therapy for treating disease symptoms in patients with chronic diseases. Quercetin is a plant flavonoid with potent antioxidant, anti-inflammatory, anti-infectious, anti-hypertensive, and blood glucose-lowering properties. Daily oral treatment with low levels of quercetin not only decreases oxidative stress and inflammation and prevents lung disease progression, but also inhibits rhinovirus-induced epithelial damage and rhinovirus replication, a major cause of COPD exacerbations. A small, double-blind, placebo-controlled clinical trial was conducted to determine the efficacy of quercetin in reducing markers of oxidative stress and inflammation in the lung in patients with COPD. The study enrolled 14 patients with COPD between 40% and 70% predicted and randomized to placebo or quercetin 2000 mg/day in a 1:2 ratio. Patients taking quercetin, but not placebo, showed significantly reduced levels of IL-8, IL-1β, and 8-isoprostane in bronchoalveolar lavage (BAL) and surfactant protein-D (SP-D) in serum. C-reactive protein (CRP) levels did not change in either group.

Pharmacologic Interventions

Oral and inhaled medications are used for patients with stable COPD to reduce dyspnea, improve exercise tolerance, and prevent exacerbations. There are two main options for delivery of inhaled medications, by inhalers or nebulizer.6

Hydrofluoroalkane inhalers (HFAs) contain medication in a liquid form, delivered as an aerosol spray from a pressurized canister. HFAs are portable devices that are fast-acting on the airways following one or two puffs taken over a few seconds. They require priming, shaking prior to use, coordination between actuation and inhalation, slow and steady inspiration, and breath-holding. A spacer may be helpful in delivering the full medication dose to the patient’s lungs.7

A dry-powder inhaler (DPI) is similar to HFA, but it releases a puff of dry powder instead of a liquid mist. DPI devices are breath-actuated, and the amount of medication reaching the lungs depends upon the aerosol characteristics. This is created by the patient’s inspiratory maneuver overcoming the internal resistance of the device and dispersing the dry powder medication, separating the drug from carrier particles.6 Therefore, for optimal DPI matching, it is recommended to measure a patient’s peak inspiratory flow (PIF), in addition to observing inhaler technique.8

A soft mist inhaler (SMI) is a more advanced type of inhaler that provides a measured amount of medicine in a slow-moving mist that helps the patient inhale the medicine. SMIs are portable devices that do not contain propellants and can be used in patients with lower inspiratory flow rates. SMIs also require hand–breath coordination and breath-holding.7

Nebulizers produce a fine mist of medication, for administration up to 20 minutes, and have been used for many years in COPD treatment. Nebulizers do not require priming, hand–breath coordination, or breath-holding, and aerosolize medication that the patient can inhale with regular tidal breathing. There are different types of nebulizers (jet, ultrasonic, and mesh), and each varies in speed of treatment administration, ease of operation, and portability. If a nebulizer is chosen, air-driven is preferred over oxygen-driven to avoid the potential risk of increasing partial pressure of carbon dioxide in the blood (PaCO2).9

Numerous studies have shown that incorrect inhalation device technique can compromise medication delivery, increase the risk of exacerbations, result in higher healthcare resource utilization, and lead to premature mortality.10,11

Despite current pharmacologic strategies with first- and second-line approaches, many patients with COPD remain symptomatic, with persistent symptoms and/or acute exacerbations as well as progressive loss of lung function, highlighting unmet needs in COPD management. Type 2 inflammation is seen in 20%–40% of patients with COPD and is one of the hallmarks of underlying pathophysiology leading to disease progression. Several novel therapeutics target type 2 inflammation (IL-4, IL-5, and IL-13) and the epithelial alarmins (IL-33 and TSLP) that contribute to the clinical features of COPD, and may help provide a tailored approach to treatment.2

Monoclonal Antibodies (mAbs)
Dupilumab

Dupilumab, the first US Food and Drug Administration (FDA)-approved biologic as an add-on treatment of uncontrolled COPD with an eosinophilic phenotype, is an mAb that inhibits the signaling action of IL-4 and IL-13 through binding of the IL-4R⍺ subunit of receptor complexes IL-4R⍺/𝝲C and IL-4R⍺/IL-13R. In symptomatic patients with elevated eosinophils on triple therapy, the addition of dupilumab resulted in fewer COPD exacerbations (graph), better lung function, and improved quality of life.16,17

 

The FDA approval of dupilumab was based on the BOREAS (N = 939) and NOTUS (N = 935) trials, which were double-blind, randomized, phase 3 trials of adults with blood eosinophil counts of ≥ 300/mL, with a primary endpoint of annualized rate of moderate to severe COPD exacerbations.16-18 Enrollment for both trials included adults who were current or former smokers aged 40 to 85 years and randomized to receive dupilumab or placebo added to maximal standard-of-care inhaled therapy.17-18 NOTUS confirmed the results from BOREAS; patients receiving dupilumab compared to placebo experienced:17-18

  • A 30% (BOREAS, P = .0005) and 34% (NOTUS, P = .0002) reduction in moderate or severe acute COPD exacerbations over 52 weeks
  • Improved lung function from baseline, by 160 mL (BOREAS, P < .0001) and 139 mL (NOTUS, P = .0001) at 12 weeks compared to 77 mL and 57 mL for placebo, respectively, with the benefit versus placebo sustained at Week 52 for both trials (BOREAS mean difference 83 mL over placebo, P = .0003; NOTUS 115 mL dupilumab vs 54 mL placebo, P = .0182).

Safety results were generally consistent with the known safety profile of dupilumab in its approved indications.18 Overall rates of adverse events (AEs in the NOTUS trial) were 67% for dupilumab and 66% for placebo.18 AEs more commonly observed with dupilumab (≥ 5% and ≥ 1% imbalance) compared to placebo included COVID-19 (9.4% dupilumab, 8.2% placebo), nasopharyngitis (6.2% dupilumab, 5.2% placebo), and headache (7.5% dupilumab, 6.5% placebo).18 While headache was more common with dupilumab (8.1% vs 6.8% placebo), AEs more commonly observed with placebo compared to dupilumab in BOREAS included upper respiratory infection (9.8% placebo vs 7.9% dupilumab) and hypertension (6% placebo vs 3.6% dupilumab).18 The proportion of patients with AEs leading to deaths were 1.5% for dupilumab and 1.7% for placebo.17-18 The overall AE profile for NOTUS was consistent with that of BOREAS.18

Mepolizumab19

Mepolizumab is an mAb that inhibits IL-5 activity through direct cytokine binding. A meta-analysis from two phase 3 clinical trials, METREX and METREO, evaluated patients with blood eosinophil counts ≥150 cells/µL at screening or ≥ 300 cells/µL in the prior year. In total, 1510 patients were randomized in METREX and METREO, and 1136 patients were included in the pre-specified meta-analysis. Mepolizumab 100 mg subcutaneous (SC) significantly reduced annual moderate/severe exacerbation rates versus placebo by 18% (rate ratio: 0.82 [95% CI, 0.71-0.95]; P = .006) and delayed time to first moderate/severe exacerbation (hazard ratio: 0.80 [0.68-0.94]; P = .006). Mepolizumab 100 mg subcutaneous (SC) versus placebo numerically reduced exacerbations leading to emergency department visits/hospitalization, and improved patient health-related quality of life.

Benralizumab20

Benralizumab is another mAb that targets IL-5 activity by inhibiting binding of the IL-5R⍺ subunit of receptor complexes on eosinophils and basophils. GALATHEA (Benralizumab Efficacy in Moderate-to-Very Severe Chronic Obstructive Pulmonary Disease with Exacerbation History; N = 1044) and TERRANOVA (Efficacy and Safety of Benralizumab in Moderate-to-Very Severe Chronic Obstructive Pulmonary Disease with Exacerbation History; N = 1392) were two phase 3, double-blind, randomized, placebo-controlled trials. The primary endpoint was the effect of benralizumab on COPD exacerbation rates. Patients aged 40–85 years were assigned into an eosinophilic (> 220 cells/μL) or non-eosinophilic (< 220 cells/μL) group.

Results of the GALATHEA study showed no significant improvements in annual rate ratios for exacerbations at any treatment dose. The same trend was detected in the TERRANOVA study. No dose effect related to benralizumab efficacy was detected, and similar adverse events were observed across studies. A patient subtype, with baseline blood eosinophil count ≥ 220 cells/mm, ≥ 3 exacerbations in the prior year, and receiving triple therapy, were the best responders, with exacerbation reductions with benralizumab (0.70; [95% CI, 0.56-0.88]).

Itepekimab

Itepekimab is an mAb that inhibits alarmin IL-33 through direct binding, A double-blind, phase 2a trial compared itepekimab (n = 172) with placebo (n = 171) in patients with moderate to severe COPD despite standard therapy, at 83 study sites in ten countries.21,22 Patients aged 40–75 years who were current or former smokers, had been diagnosed with COPD for at least 1 year, and were on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy were randomly assigned to receive itepekimab 300 mg or placebo, administered as two subcutaneous injections every 2 weeks for 24–52 weeks. Annualized rates of acute exacerbations of COPD were lower in the itepekimab group (1.30, [1.05–1.61]) vs placebo (1.61, [1.32–1.97]), with a relative risk of (0.81 [0.61–1·07]; P = .13).21 When the analysis was restricted to former smokers, treatment with itepekimab was associated with nominally significant reductions in acute exacerbations of COPD (RR .58, [95% CI, 0.39–0.85]; P = .0061) and FEV1 improvement (least squares mean difference .09 L [.02–.15], P = .0076) compared with placebo.21 Two phase 3 clinical studies are ongoing to confirm the efficacy and safety profile of itepekimab in former smokers with COPD.21

Astegolimab

Astegolimab is an mAb that inhibits IL-33 activity by binding to its receptor, ST2, on parenchymal and inflammatory cells.12 In the single-center, randomized, double-blind, placebo-controlled COPD-ST2OP trial (phase 2a, N = 81), participants with moderate to very severe COPD were randomly assigned (1:1) to astegolimab 490 mg SC or placebo every (q) 4 weeks over 44 weeks.23,24 At 48 weeks, overall exacerbation rates between the astegolimab and placebo arms were not significantly different (2.18 vs 2.81; P = .19) or in prespecified groups with high (> 170 cells/µL) or low (< 170 cells/µL) eosinophil counts (0.83 [0.49-1.40] vs .0.69 [0.39-1.21]). While astegolimab was not found to significantly reduce exacerbation rates, the health status of participants did improve compared with placebo.23

Tozorakimab is a promising monoclonal antibody under investigation for the treatment of COPD. It targets IL-13. It is a broad-acting epithelial “alarmin” cytokine targeting IL-33. Early safety, pharmacokinetic, and biomarker studies support the clinical development of this monoclonal antibody.25 Phase 2 data from FRONTIER-4 suggests that tozorakimab may improve lung function and reduce COPD exacerbations, especially in patients with frequent exacerbation history.26

Tezepelumab

Tezepelumab is an mAb that targets thymic stromal lymphopoetin (TSLP) through direct binding, inhibiting TSLP binding with its receptor. In a phase 2, randomized, double-blind trial, tezepelumab was evaluated over 52 weeks using 3 dosing levels (70 mg, N = 138; 210 mg, N = 137; 280 mg, N = 137) compared to placebo.27 Researchers reported a significant diminution of annualized asthma exacerbation rates for tezepelumab over placebo (62% dosed at 70 mg q4 weeks, 71% dosed at 210 mg q4 weeks, and 66% dosed at 280 mg q2 weeks; P < .001).27 Pre-bronchodilator FEV1 was also slightly higher in all tezepelumab-treated groups, independent of baseline blood eosinophil counts.27 Currently, COURSE (Tezepelumab COPD Exacerbation Study), a phase 2a, multicenter, double-blind, randomized trial, is recruiting patients to assess the efficacy of tezepelumab on moderate or severe COPD exacerbation rate ratios.28

Additional Targeted Approaches
Danirixin13

Danirixin is a selective and reversible CXC chemokine receptor 2 antagonist that may be useful for the treatment of respiratory diseases such as COPD. A randomized, phase 2 study (N = 93) conducted over 52 weeks assessed the effects of danirixin when added to standard of care inhaled therapy in participants with symptomatic COPD. Participants had comparable Evaluating Respiratory Symptoms (E-RS): COPD total scores at baseline (12.1 ± 5.74 danirixin, 12.1 ± 5.79 placebo). Decreases in the E-RS: COPD total score were observed with danirixin within 2 months of study start, and were maintained through 52 weeks (11.16 danirixin, 12.67 placebo). Duration of experienced exacerbations were also shorter in the danirixin group (median 9 days vs 17 days placebo).

Nemiralisib

Nemiralisib is a potent and highly selective phosphoinositide 3-kinase δ (PI3Kδ) inhibitor that has been investigated as an immunomodulatory agent with anti-inflammatory properties in COPD.  In a double-blind, placebo-controlled, phase 2b study, COPD patients (40–80 years, ≥ 10 pack-year smoking history, with current moderate/severe acute exacerbation of COPD requiring standard-of-care treatment) were randomized to either placebo or nemiralisib.14 There was no difference in change from baseline FEV1 at week 12 between the nemiralisib and placebo treatment groups (-0.004L, CrI, -0.051L-0.042L; posterior adjusted median difference, nemiralisib 750 µg and placebo). Overall, there were also no differences between nemiralisib and placebo in secondary endpoints, including re-exacerbations.14 This study was terminated due to an unfavorable benefit to risk ratio.15

Combination Therapy
ICS/LAMA/LABA

The recent phase 3 IMPACT and ETHOS clinical trials found mortality benefits with inhaled corticosteroid/long-acting muscarinic receptor antagonist/long-acting β2 agonist (ICS/LAMA/LABA) triple therapy compared with LAMA/LABA dual therapy in patient populations with symptomatic COPD at high risk of future exacerbations.29

References

  1. Agarwal AK, Raja A, Brown BD. Chronic obstructive pulmonary disease. StatPearls. 2023. Last update 8/7/23. https://www.ncbi.nlm.nih.gov/books/NBK559281/
  2. Rabe KF, Rennard S, Martinez FJ, et al. Targeting type 2 inflammation and epithelial alarmins in chronic obstructive pulmonary disease: a biologics outlook. Am J Respir Crit Care Med. 2023;208:395-405.
  3. Agusti A, Celli B, Criner G, et al. Global Initiative for Chronic Obstructive Lung Disease 2023 Report: GOLD Executive Summary. Am J Respir Crit Care Med. 2023;207:819-837.
  4. Hsieh MJ, Yang TM, Tsai YH. Nutritional supplementation in patients with chronic obstructive pulmonary disease. J Formos Med Assoc. 2016;115(8):595-601.
  5. Patel S, Marchetti N, et al. Oral treatment with quercetin reduces markers of inflammation in COPD patients. Am J Respir Crit Care Med. 2023;207:A5001.
  6. Telko M, Hickey A. Dry powder inhaler formulation. Care. 2005;50:1209-1227.
  7. Brand P, Hederer B, Austen G, Dewberry H, Meyer T. Higher lung deposition with Respimat Soft Mist inhaler than HFA-MDI in COPD patients with poor technique. Int J Chron Obstruct Pulmon Dis. 2008;3:763‑770.
  8. Leving M, Bosnic-Anticevich S, van Cooten J, et al. Clinical recommendations for dry powder inhaler use in the management of COPD in primary care. NPJ Prim Care Respir Med. 2022;32:59-67.
  9. Ari A. Jet, ultrasonic, and mesh nebulizers: an evaluation of nebulizers for better clinical outcomes. Eur J Pulmonol. 2014;16:1-7.
  10. Molimard M, Raherison C, Lignot S, et al. Chronic obstructive pulmonary disease exacerbation and inhaler device handling: real-life assessment of 2935 patients. Eur Respir J. 2017;49:1601794.
  11. Maricoto T, Montiero L, Gama J, et al. Inhaler technique education and exacerbation risk in older adults with asthma or chronic obstructive pulmonary disease: a meta-analysis. J Am Geriatr Soc. 2019;67:57-66.
  12. Kelsen SG, et al. Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: a randomized clinical trial. J Allergy Clin Immunol. 2021;148:790-798.
  13. Lazaar A, Miller B, Tabberer M, et al. Effect of the CXCR2 antagonist danirixin on symptoms and health status in COPD. Eur Respir J. 2018;52:1801020.
  14. Fahy W, Homayoun-Valiani F, Cahn A, et al. Nemiralisib in patients with an acute exacerbation of COPD: placebo-controlled, dose-ranging study. Int J Chron Obstruct Pulmon Dis. 2021;16:1637-1646.
  15. ClinicalTrials.gov. Dose Finding Study of Nemiralisib (GSK2269557) in Subjects With an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD). https://www.clinicaltrials.gov/study/NCT03345407
  16. Dupilumab (Dupixent®) Prescribing Information (PI) 2024 (www.regeneron.com/downloads/dupixent_fpi.pdf).
  17. Bhatt S, Rabe K, Hanania N, et al. Dupilumab for COPD with type 2 inflammation indicated by elevated eosinophils. N Engl J Med. 2023;389:205-214.
  18. Sanofi: Dupixent® significantly reduced COPD exacerbations in second positive Phase 3 trial, accelerating FDA submission and confirming potential to become first approved biologic for this serious disease. Sanofi. November 27, 2023. https://www.sanofi.com/en/media-room/press-releases/2023/2023-11-27-06-30-00-2785836
  19. Pavord I, Chapman K, Bafadhel M, et al. Mepolizumab for eosinophil-associated COPD: analysis of METREX and METREO. Int J Chron Obstruct Pulm Dis. 2021;16:1755-1770.
  20. Criner GJ, Celli BR, Singh D, et al. Predicting response to benralizumab in chronic obstructive pulmonary disease: analyses of GALATHEA and TERRANOVA studies. Lancet Respir Med. 2020;8:158-170.
  21. Rabe K, Celli B, Wechsler M, et al. Safety and efficacy of itepekimab in patients with moderate-to-severe COPD: a genetic association study and randomised, double-blind, phase 2a trial. Lancet Respir Med. 2021;9:1288-1298.
  22. ClinicalTrials.gov. Proof-of-Concept Study to Assess the Efficacy, Safety and Tolerability of SAR440340 (Anti-IL-33 mAb) in Patients With Moderate-to-severe Chronic Obstructive Pulmonary Disease (COPD). https://clinicaltrials.gov/study/NCT03546907
  23. Yousuf AJ, et al. Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial. Lancet Respir Med. 2022;10:469-477.
  24. ClinicalTrials.gov. Anti-ST2 (MSTT1041A) in COPD (COPD-ST2OP). https://clinicaltrials.gov/study/NCT03615040
  25. Reid F, Singh D, Albayaty M, et al. A randomized phase I study of the anti-interleukin-33 antibody tozorakimab in healthy adults and patients with chronic obstructive pulmonary disease. Clin Pharmacol Ther. 2024;115(3):565-575.
  26. Singh D, Guller P, Reid F, et al. S92 FRONTIER-4: a phase 2a study to investigate tozorakimab (anti-IL-33 mAb) in COPD. Thorax. 2024;79:A68.
  27. Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377:936-946.
  28. ClinicalTrials.gov. Tezepelumab. COPD Exacerbation Study. https://clinicaltrials.gov/study/NCT04039113
  29. Mintz M, Barjaktarevic I, Mahler D, et al. Reducing the risk of mortality in chronic obstructive pulmonary disease with pharmacotherapy: A narrative review. Mayo Clin Proc. 2023;98:301-315.

All URLs accessed March 10, 2025.

Epidemiology

Pathophysiology

Guidelines

Treating and Managing COPD

Individualized Care Strategies

Smoking Cessation

Additional Resources

This activity is provided by Med Learning Group.
This activity is supported by an independent medical education grant from Regeneron Pharmaceuticals, Inc. and Sanofi.

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