Stephanie Christenson, MD: An "Exciting" New Era in COPD Management

After a pair of historic approvals in 2024, the pulmonology community heads into 2025 with a revamped armamentarium boasting new options for chronic obstructive pulmonary disease (COPD) management, including the first biologic therapy ever approved for the condition with ensifentrine (Ohtuvayre) and dupilumab (Dupixent).¹

“There's so many people that are still suffering,” said Stephanie Christenson, MD, associate professor of medicine at the University of California, San Francisco, in an interview with HCPLive. “So, I think for these different groups of people, where we can potentially have additional drugs to offer to maybe improve quality of life, keep you out of the hospital, even decrease mortality in the long run—if we can decrease severe exacerbations, or even moderate exacerbations, which do increase your risk of mortality—I'm very much on board with trying some of these different drugs. Especially, a lot of these drugs that have shown to be very safe, and we'll see what some of the other ones that are coming down the pipeline.”

Leading up to summer 2024, the US pulmonology community had its eyes fixed upon on the week of June 24, 2024, which had the potential to see a pair of historic COPD approvals in subsequent days, with PDUFAs for ensifentrine on June 26, 2024 and dupilumab on June 27, 2024. Ensifentrine would go on to receive approval from the US Food and Drug Administration (FDA) for on its original June 26, 2024 PDUFA date. With approval, ensifentrine became is the first inhaled product with a novel mechanism of action available for the maintenance treatment of COPD in more than 20 years.^1,2

In May, Regeneron announced the extension of the review period for the supplemental Biologics License Application for dupilumab in COPD until September. On September 27, 2024, dupilumab received approval from the FDA as an add-on maintenance treatment for adults with inadequately COPD and an eosinophilic phenotype based on data from the BOREAS and NOTUS trial.¹

Ensifentrine’s Supporting Data

The approval of ensifentrine, a first-in-class selective dual inhibitor of the enzymes phosphodiesterase 3 and phosphodiesterase 4, was based on data from the ENHANCE-1 and ENHANCE-2 trials. Both designed as multicenter, randomized, double-blind, parallel-group, placebo-controlled trials, ENHANCE-1 and ENHANCE-2 enrolled 1549 patients 40 to 80 years of age with moderate to severe symptomatic COPD. Conducted between September 2020 and December 2022 at 250 sites in 17 countries, the trial randomized patients 1:1 and used post-bronchodilator FEV₁ area under the curve as the primary outcome of interest.³

Results of the trials suggested ensifentrine significantly improved average FEV₁ area under the curve at 0 to 12 hours relative to placebo in both ENHANCE-1 (87 mL; 95% confidence interval (CI), 55 to 119) and ENHANCE-2 (94 mL; 95% CI, 65 to 124) (P for both < .001).³

In secondary analyses, also demonstrated use of ensifentrine was associated with a reduced the rate of moderate or severe exacerbations relative to placebo at 24 weeks in both the ENHANCE-1 (Rate Ratio [RR], 0.64; 95% CI, 0.40 to 1.00; P = .050) and ENHANCE-2 (RR, 0.57; 95% CI, 0.38 to 0.87; P = .009) trials. Additionally, use of ensifentrine was associated with an increased time to first exacerbation in both the ENHANCE-1 (hazard ratio [HR], 0.62; 95% CI, 0.39 to 0.97; P = .038) and ENHANCE-2 (HR, 0.58; 95% CI, 0.38 to 0.87; P = .009) trials.³

Dupilumab’s Supporting Data

The approval of dupilumab was based on the phase 3 BOREAS and NOTUS trials. The primary outcome of interest for both trials was the rate of moderate or severe acute COPD exacerbations at 52 weeks.^4,5

The BOREAS trial was a double-blind, randomized, placebo-controlled study involving 939 current or former smokers with physician-diagnosed COPD and blood eosinophils of 300 mL or greater aged 40 to 80, conducted across 275 sites in 24 countries. The trial concluded dupilumab reduced moderate or severe acute COPD exacerbations by 30% compared to placebo (RR, 0.70; 95% CI, 0.58 to 0.86; P = .0005).⁴

Results suggested use of dupilumab improved lung function, with prebronchodilator FEV₁ increasing by 160 mL in the dupilumab arm compared to 77 mL for placebo (P < .0001) at 12 weeks. When announcing trial results, Regeneron noted improvements in health-related quality of life and symptom severity, as measured by the SGRQ and E-RS COPD scales.^4,6

The NOTUS trial closely mirrored BOREAS but included participants aged 40 to 85 years. Conducted at 329 sites in 29 countries, the placebo-controlled trial randomized 935 patients. Results showed dupilumab reduced moderate or severe COPD exacerbations by 34% (P < .001) and improved lung function with an FEV1 increase of 139 mL compared to 57 mL for placebo (P < .001). At the time of study release, Regeneron called attention to numeric improvements in quality of life and respiratory symptom severity seen in this study.^5,7

Relevant disclosures for Christenson include Sanofi, AstraZeneca, Genzyme, GlaxoSmithKline, and Regeneron.

References:

1. Regeneron Pharmaceuticals Inc. Dupixent® (dupilumab) approved in the U.S. as the first-ever biologic medicine for patients with COPD. Regeneron Pharmaceuticals Inc. September 27, 2024. Accessed September 30, 2024. https://investor.regeneron.com/news-releases/news-release-details/dupixentr-dupilumab-approved-us-first-ever-biologic-medicine.
2. Verona Pharma. Verona Pharma announces US FDA approval of OhtuvayreTM (Ensifentrine). Verona Pharma. June 26, 2024. Accessed September 30, 2024. https://www.veronapharma.com/news/verona-pharma-announces-us-fda-approval-of-ohtuvayre-ensifentrine/.
3. Anzueto A, Barjaktarevic IZ, Siler TM, 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):406-416. doi:10.1164/rccm.202306-0944OC
4. 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
5. Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation. N Engl J Med. 2024;390(24):2274-2283. doi:10.1056/NEJMoa2401304
6. Regeneron Pharmaceuticals Inc. Dupixent® (dupilumab) demonstrates potential to become first biologic to treat COPD by showing significant reduction in exacerbations in pivotal trial. Regeneron Pharmaceuticals Inc. March 23, 2023. Accessed September 30, 2024. https://investor.regeneron.com/news-releases/news-release-details/dupixentr-dupilumab-demonstrates-potential-become-first-biologic.
7. Regeneron Pharmaceuticals Inc. Dupixent® (dupilumab) late-breaking data from Notus Confirmatory Phase 3 COPD trial presented at ATS and published in the New England Journal of Medicine. Regeneron Pharmaceuticals Inc. May 20, 2024. Accessed September 30, 2024. https://investor.regeneron.com/news-releases/news-release-details/dupixentr-dupilumab-late-breaking-data-notus-confirmatory-phase.