By Brooks T. Kuhn, MD, MAS, and Timothy E. Albertson, MD, MPH, PhD

Patients with chronic obstructive pulmonary disease (COPD) have long suffered from the self-fulfilling prophecy of low expectations. An inhaler prescription, pat on the back, and good-luck wishes have sufficed as the standard of care for far too long. While hospital readmission rates and length of stay and even mortality have improved for other conditions, such as heart disease and cancer, little has changed over the prior decades for patients with COPD.

There are many reasons behind the nihilism in COPD: indifference for a self-inflicted disease, competing interest with comorbid conditions, and — until recently — a paucity of effective medications. The under-prescription of azithromycin stands as a testament that the lack of medications alone is not the problem. For over a decade, there has been considerable evidence from multiple randomized clinical trials demonstrating the benefit of azithromycin in suppressing COPD exacerbation frequency by 20%–30%, yet very few patients who meet the criteria are actually prescribed this affordable and relatively well-tolerated drug.

Fortunately, instead of collapsing this complex disease into a single diagnosis, there's been a move toward identifying treatable traits, including endotypes (subgroups characterized by distinct biologic mechanisms) and phenotypes (subgroups defined by clinical constellations of findings). Programs such as pulmonary rehabilitation and dedicated COPD clinics benefit in large part due to personalized care achieved by tailoring the myriad, incrementally beneficial therapies available for this disease (such as proper inhaler prescription and technique, airway hygiene, and safe exercise). Disappointingly, on the other hand,current-day “optimal therapy" for COPD still results in lung function and clinical decline over time.

There is cause for hope, though. As research has increased our understanding of airway biology, novel and hopefully more impactful therapies have and will arise. In just the past year, the Food and Drug Administration (FDA) has approved two new medications — dupilumab and ensifentrine — for the management of patients with COPD, changing for the better our definition of “optimal therapy.”

The New Biologics in Town

Dupilumab is a monoclonal antibody that inhibits interleukin-4 and interleukin-13, subsequently decreasing allergic (often called type 2) inflammation. Two large, randomized clinical trials (BOREAS and NOTUS) demonstrated that in patients with elevated blood eosinophils — a marker of type 2 inflammation — patients receiving dupilumab every 2 weeks demonstrated fewer exacerbations, increased lung function, and improved symptoms. While approved by FDA for COPD this past September, dupilumab has been in clinical use since 2018 for asthma and other indications, such as atopic dermatitis and nasal polyposis. Adverse events for patients receiving dupilumab were similar to the control arm and notably much better than the ill effects of oral corticosteroids.

This is not the first trial for so-called “biologics” in COPD. Multiple studies have been performed targeting interleukin-5 with conflicting and as-of-yet unconvincing impact on clinical outcomes. As we learn more about the airway biology of COPD, new therapies are likely to arise targeting type 2 inflammation and other endotypes. Promisingly, there are a number of ongoing trials investigating similar targeted approaches to other mediators of inflammation of the COPD airway, including thymic stromal lymphopoietin and interleukin-33.

Ensifentrine is another new medication in our toolkit to manage COPD. It is a twice-per-day nebulized medication that targets phosphodiesterase receptors 3 and 4. While currently available therapies such as theophylline and roflumilast target phosphodiesterase receptors, the use of these two agents has been limited largely due to a narrow therapeutic range, commonly manifest with gastrointestinal side effects and weight loss. Ensifentrine targets PDE 3 and 4, impairing neutrophilic inflammation within the lungs as well as providing bronchodilation in a pathway independent of our commonly used adrenergic (i.e., beta-agonists) and muscarinic modulation. The ENHANCE trial studied ensifentrine in moderate-to-severe COPD and showed improvement in lung function, symptoms, and quality of life, as well as a reduction in moderate-to-severe exacerbations, although many patients enrolled in the study were on only single- or double-inhaled background therapies. Ensifentrine was well tolerated — especially compared to the oral agents in this class — without increased GI adverse effects compared with placebo.

While both dupilumab and ensifentrine have shown benefit in select situations, their exact role in COPD treatment algorithms is still unsettled. Despite these advances, significant challenges remain, including immediacy bias in treatment (i.e., a focus on treating a single exacerbation acutely, not seeing it as a failure of prior chronic therapy) and high medication costs, especially with dupilumab and ensifentrine exacerbating social and economic gaps due to barriers in access. Another challenge is identifying patients previously told they were on “optimal” therapy, which may not be the case with new medications and therapies available.

The Bigger Picture

While these new therapies are important and aid clinicians in providing better care for their patients with COPD, the impact can go beyond direct patient care. Better therapies can come with a stronger argument for earlier and more robust screening, increased attention and focus from front-line providers, and institutional resources and care infrastructure from healthcare systems needed for the increasingly complicated care of patients with COPD. Future potentially disease course-altering therapies may even change the nihilistic presumption that COPD care treats self-inflicted, irreversible damage. Most importantly, novel therapies provide clinicians with hope, which remains our most important therapeutic tool to treat patients struggling with COPD.

REFERENCES: 

Bhatt SP, Rabe KF, Hanania NA, Vogelmeier CF, Cole J, Bafadhel M et al. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N Engl J Med. 2023;389(3):205-14. doi:10.1056/NEJMoa2303951.

Bhatt SP, Rabe KF, Hanania NA, Vogelmeier CF, Bafadhel M, Christenson SA et al. Dupilumab for COPD with blood eosinophil evidence of type 2 inflammation. N Engl J Med. 2024. doi:10.1056/NEJMoa2401304.

Anzueto A, Barjaktarevic IZ, Siler TM, Rheault T, Bengtsson T, Rickard K et al. Ensifentrine, a novel phosphodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE Trials). Am J Respir Crit Care Med. 2023;208(4):406-16. doi:10.1164/rccm.202306-0944OC.

Drs. Kuhn and Albertson are both affiliated with the Division of Pulmonary, Critical Care, and Sleep Medicine, UC Davis, School of Medicine in Sacramento, California.