On September 27, the US Food and Drug Administration (FDA) approved dupilumab (Dupixent, Sanofi/Regeneron) as an add-on maintenance treatment for adult patients with uncontrolled chronic obstructive pulmonary disease (COPD). Dupilumab is the first biologic medicine approved in the US for COPD. The US FDA approval follows that of the European Union and China.
The agency granted dupilumab Priority Review for this indication, a designation given to regulatory applications seeking approval for therapies that have the potential to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Dupilumab is also FDA-approved for various other conditions, including atopic dermatitis, asthma, eosinophilic esophagitis, prurigo nodularis, and chronic rhinosinusitis with nasal polyposis (more on rhinosinusitis indication below).
Dupilumab’s Mechanism in COPD Treatment
Dupilumab is a fully human monoclonal antibody that inhibits the interleukin (IL)-4 and IL-13 pathways. Some patients with COPD demonstrate type 2 inflammation, exhibited by elevated cytokines and immune cells, most commonly including IL-5, IL-4, IL-13, type 2 innate lymphoid cells, and type 2 helper T cells. Increased levels of these substances can cause elevated eosinophil counts in sputum, bronchial tissue, and blood or elevated levels of fractional exhaled nitric oxide (FeNO).
The IL-4 and IL-13 pathways specifically increase the FeNO level and promote eosinophil and type 2 inflammatory cell infiltrates in the lungs specifically. These infiltrates are believed to cause airway hyperreactivity, impairment of epithelial barrier function, fibrosis, and airway remodeling; lung-function decline; goblet-cell hyperplasia; mucociliary dysfunction; and mucus hypersecretion. In short, type 2 inflammation in patients with COPD increases the risk of exacerbation.
Clinical Trials Show Reduced Exacerbation Rates
The FDA based its decision on the results from the phase 3 BOREAS and NOTUS clinical trials. The BOREAS study enrolled 939 patients with COPD who had elevated blood eosinophil counts (≥ 300 per microliter) and an increased risk of exacerbations despite standard triple therapy with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting beta-2 agonist (LABA).
Researchers randomized participants to receive dupilumab 300 mg every two weeks (n = 468) or placebo (n = 471). Results showed that the dupilumab group had a significantly lower exacerbation rate compared to the placebo group (0.78 vs 1.10; P < 0.001). Dupilumab also improved lung function, with patients showing a greater increase in forced expiratory volume in 1 second (FEV1) at 12 weeks, and this improvement lasted through the year-long study (P < 0.001 at week 12; P = 0.001 at week 52). Quality of life and respiratory symptoms also improved more in the dupilumab group compared to placebo. Both groups had similar rates of adverse events leading to discontinuation, serious adverse events, and deaths.
Similarly, the NOTUS trial enrolled 935 patients with COPD who had elevated blood eosinophil counts (≥ 300 per microliter). Researchers randomized participants to receive dupilumab 300 mg every two weeks (n = 470) or placebo (n = 465). Results showed a significantly lower exacerbation rate the dupilumab group compared to the placebo group (0.86 vs 1.30; P < 0.001).
Dupilumab also improved lung function, with patients showing a greater increase in FEV1 at 12 weeks, and this improvement was sustained through the year-long study (P < 0.001 at week 12; P = 0.02 at week 52). However, no significant difference was observed in quality-of-life scores between the two groups. Both groups experienced a similar incidence of adverse events, consistent with the dupilumab’s established safety profile.
Adverse events more commonly observed with dupixent (≥5%) compared to placebo in either COPD trial were back pain, COVID-19, diarrhea, headache, and nasopharyngitis.
Adding to the Armamentarium of Novel COPD Therapies
Dupilumab’s approval comes on the heels of another novel therapy approval for COPD, ensifentrine (Ohtuvayre, Verona Pharma). Both ensifentrine and dupilumab have demonstrated significant improvements in lung function for patients with COPD. However, ensifentrine acts primarily as a bronchodilator, while dupilumab targets type 2 inflammation and significantly reduces exacerbation rates. This makes dupilumab particularly beneficial for patients with elevated eosinophil counts, while ensifentrine is best suited for patients who require enhanced bronchodilation, especially those with moderate to severe disease who may not fully respond to standard therapies.
Additional biologic medications for COPD are in late-stage trials by AstraZeneca (tezepelumab) and Roche (astegolimab).
Dupilumab Also Gets FDA Nod for Chronic Rhinosinusitis in Adolescents
In a separate decision issued earlier this month, the FDA extended dupilumab’s indication for the treatment of chronic rhinosinusitis with nasal polyps to pediatric patients aged 12 to 17 years. Originally approved for adults in 2019 as an add-on maintenance treatment in those patients with uncontrolled disease, the extended indication marks the first drug approval for chronic rhinosinusitis in an adolescent population. Approximately 9,000 adolescents are affected by the condition.
