More Biologics Breaking Through for COPD

New biologic drugs for chronic obstructive pulmonary disease (COPD) are finally here, said Stephen Rennard, MD, in a presentation in a session on new drugs at the 2024 GOLD International COPD Conference.

The inflammatory pathways associated with COPD are diverse and offer a range of potential targets for biologics, said Rennard, a professor of pulmonary, critical care, and sleep medicine at the University of Nebraska Medical Center, Omaha, Nebraska.

The therapeutic goals of biologics remain the same as with other treatments for COPD, namely restoration of normal inflammatory response and alteration of disease progression, as well as restoration of lost structure and function and improvement of systemic effects, Rennard said in his presentation. Most studies of new and up-and-coming drugs have improvement in acute exacerbation of COPD as the primary outcome, he added.

The Biology Behind the Biologics

T2 inflammation is “an inflammatory cascade led by IL-4, IL-13, and IL-5,” Mona Bafadhel, MD, chair of Respiratory Medicine at King’s College London, London, England, said in her presentation during the session.

Bafadhel, who served as one of the investigators on the BOREAS and NOTUS studies, explained some of the science behind the development of the new biologics.

Eosinophils are powerful regulators of immune response and inflammation by stimulating T-cell production and affecting other immune cell types, she noted.

In the context of COPD and drug development, high blood eosinophil counts have been associated with increased COPD-related exacerbations, Bafadhel said. She cited data from a Dutch study of more than 7000 patients with COPD (with and without clinical diagnoses), in which absolute eosinophil counts ≥ 3.3% were associated with increased risk for severe exacerbations of 32% and 84% across all patients with COPD and clinical COPD, respectively.

Understanding the mechanisms of the eosinophil in COPD is important for research and development, Bafadhel said. Along with standardizing measurement of T2 inflammatory markers (interleukin [IL] 4, IL-13, and IL-5), more research is needed to fully understand the role of eosinophils in immunoregulation and repair, she noted.

Fitting the Biologic to the Patient

Several recent studies of up-and-coming biologics have focused on subsets of COPD patients, said Dave Singh, MD, professor of clinical pharmacology and respiratory medicine at The University of Manchester, Manchester, England, in his presentation at the meeting. In September 2024, the US Food and Drug Administration (FDA) approved dupilumab as the first biologic treatment for patients with uncontrolled COPD and type 2 inflammation on the basis of eosinophil counts. Singh cited data from the BOREAS and NOTUS studies in which dupilumab significantly reduced exacerbations and improved lung function in these patients compared with a placebo.

Mepolizumab, a biologic approved for asthma, is not currently approved for COPD, but data from a 2017 study showed a trend toward reduced exacerbations compared with placebo in a subset of patients with high blood eosinophil counts, Singh said.

In addition, a recent unpublished phase 3 study (MATINEE) showed a reduction in the annualized rate of exacerbations compared with placebo on the basis of up to 2 years’ follow-up.

Singh also highlighted data from a phase 2a study of astegolimab, a biologic drug that focuses on the IL-33 receptor, in which COPD exacerbation rates were not significantly different between treatment and placebo groups. However, astegolimab has shown safety and efficacy in adults with severe asthma and is under development in phase 3 trials for COPD.

Tezepelumab, which was approved by the FDA in 2021 as an add-on therapy for severe asthma in patients aged 12 years or older, is also in development as a therapy for COPD exacerbations, Singh said.

In a study presented at the 2024 American Thoracic Society annual meeting, Singh and colleagues found that tezepelumab at a subcutaneous dose of 420 mg every 4 weeks reduced the annualized rate of moderate or severe COPD exacerbations compared with placebo based on data from approximately 300 patients, although the difference was not statistically significant.

Itepekimab, another biologic, showed promise in a phase 2a genetic association study involving current and former smokers with moderate to severe COPD, Singh said.

In that study, published in 2022 in The Lancet Respiratory Medicine, itepekimab failed to meet the primary endpoint in the overall study population of reduced annualized rate of moderate to severe exacerbations; however, a subgroup analysis of former smokers showed a significant (42%) reduction in exacerbations, Singh said in his presentation. Two phase 3 clinical studies (AERIFY-1/2) are ongoing to confirm the safety and efficacy of itepekimab in former smokers with COPD.

Takeaways and Next Steps

“These therapies provide the first new classes of medications approved for COPD in nearly 20 years,” said David M. Mannino, MD, of the University of Kentucky, Lexington, Kentucky, in an interview. “Dupilumab will be available to a subset of patients who are poorly controlled and have evidence of high eosinophils in their blood and is only used once every 2 weeks,” said Mannino, who has served as a consultant to companies developing COPD drugs.

Both dupilumab and ensifentrine, a phosphodiesterase (PDE) 3 and PDE4 inhibitor also recently approved for maintenance treatment of COPD, have been shown in clinical trials to reduce exacerbations and improve symptoms, said Mannino. Both offer additional options for patients who continue to have symptoms and exacerbations in spite of their current therapy, he said.

Some barriers to the use of biologics in practice include the high cost, said Mannino. “Access and overcoming insurance-related issues such as preauthorization and high copays will be a challenge,” he said. Also, because dupilumab is an injectable drug, some patient training will be required, he noted.

Newer biologic therapies in development are also injectables, but some studies are examining longer time intervals as long as every 6 months, which could be a major advancement for some patients, Mannino told Medscape Medical News. The newer therapies in development are similar to dupilumab in that they will be injected therapies. Some in development are looking at longer time intervals as long as every 6 months, which may be a major advancement for some patients, said Mannino. “All of these therapies, however, are currently targeting more advanced or serious disease,” he said.

Looking ahead, more therapies are needed for the treatment of early COPD, as well as therapies that can be administered to a large number of patients at a reasonable cost, Mannino added.

Rennard disclosed serving as a consultant for Verona Pharma, Sanofi, Beyond Air, RS BioTherapeutics, RespirAI, and Roche, as well as speaker fees from Sanofi and temporary ownership interest while employed by AstraZeneca. Rennard is also the founder of Great Plains Biometrix.

Bafadhel disclosed funding from the National Institute for Health Research (NIHR), grants from Asthma + Lung UK, Horizon Europe, NIHR, and AstraZeneca to her institution, and honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Pfizer.

Singh disclosed relationships including speaking sponsorships, honoraria, and advisory board memberships for Adovate, Aerogen, Almirall, Apogee, Arrowhead, AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, Cipla, Connect Biopharm, Covis, CSL Behring, DevPro Biopharma LLC, Elpen, Empirico, EpiEndo, Genentech, Generate Biomedicines, GlaxoSmithKline, Glenmark, Kamada, Kinaset Therapeutics, Kymera, Menarini, MicroA, OM Pharma, Orion, Pieris Pharmaceuticals, Pulmatrix, Revolo, Roivant Sciences, Sanofi, Synairgen, Tetherex, Teva, Theravance Biopharma, Upstream, and Verona Pharma.

Mannino disclosed serving as a consultant to multiple companies currently developing COPD therapies (AstraZeneca, GlaxoSmithKline, Roche, Regeneron, Sanofi, Genentech, Amgen, and Chiesi).