Dupilumab (Dupixent) by Sanofi has initially been marketed for the treatment of uncontrolled moderate-to-severe Atopic Dermatitis. Its indications have since expanded to include moderate-to-severe eosinophilic asthma, chronic rhinosinusitis with nasal polyps and more. It is a fully human monoclonal antibody that blocks the receptor components for interleukin-4 and interleukin-13, which are involved in the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD) [1].
The World Health Organisation (WHO) estimates that by 2060, more than 5.4 million deaths per year will be attributed to COPD and related conditions. Many patients still experience symptoms and exacerbations despite being on guideline recommended triple inhaler therapy (inhaled glucocorticoid, long-acting muscarinic antagonist and long acting B2 agonist). This has led to a poorer quality of life, increased hospitalisations and increased risk of death.
Type 2 inflammation is present in 20 to 40% of patients with COPD and is associated with an increased risk of exacerbations. Cytokines and immune cells that are most commonly elevated in patients with type 2 inflammation include IL-5, IL-4, IL-13, type 2 innate lymphoid cells, and type 2 helper T cells. By blocking IL-4 and IL-13 pathways, Dupilumab is postulated to reduce eosinophil and type 2 inflammation cell infiltrates in the lungs, reducing airway hyper-reactivity, airway remodelling, mucociliary dysfunction and mucus hypersecretion.
What does the BOREAS trial add to current studies in treatment of COPD?
Studies of biologic agents in the treatment of COPD have failed to show significant reduction in the number of exacerbations or improvement in lung function and quality of life. However, Dupilumab, has provided a breakthrough in the BOREAS trial.
The BOREAS trial included current or former smokers between 40-80 years old diagnosed with moderate to severe (FEV1 30-70%) COPD for at least 1 year. They had to be on stable doses of standard triple inhaler therapy and blood eosinophil of at least 300 uL. These patients also must have a high risk of exacerbations, having at least 2 moderate exacerbations or at least 1 severe exacerbation 1 year prior to screening. Patients with a diagnosis or history of asthma were excluded.
The active treatment group received subcutaneous dupilumab as add-on therapy at a dose of 300mg once every 2 weeks for 52 weeks. Patients will enter a 12 week follow up safety period after completing 52 weeks of medications.
Results
The Dupilumab group (n=468) had a 30% reduction in annualised rate of moderate or severe exacerbations compared to the placebo group (n=471), which was the primary endpoint (Figure 1).
Figure 1
Secondary endpoints were aimed at determining difference lung function and patient-reported outcomes between the Dupilumab and placebo group.
- Least square mean change from baseline in prebronchodilator FEV1 was 160 mL in the Dupilumab group and 77 mL in the placebo group. Improvement was observed within 2 weeks after treatment initiation and sustained throughout 52 weeks
- Improvement from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score at week 52 was greater in the Dupilumab group, with improvements seen as early as 4 weeks after treatment initiation
- Improvement in Evaluating Respiratory Symptoms in COPD (E-RS-COPD) total score from baseline was greater in the Dupilumab group
Least square mean change from baseline in prebronchodilator FEV1 was much greater in patients who had fractional exhaled nitric oxide (FeNO) level of 2 ppb or higher at baseline, with a change of 232 mL and 108 mL seen in the Dupilumab group and placebo group respectively (P < 0.002)
Figure 2
Safety
The incidence of adverse events were similar between the dupilumab group and placebo group. Most common adverse events were nasopharyngitis, upper respiratory tract infection and headache.
Adverse events commonly associated with COPD include respiratory, cardiac and vascular events. Incidence of adverse event across all organ classes were largely similar between dupilumab group and placebo group
Summary
Through the results of this trial has concluded that Dupilumab can be used in symptomatic COPD patients with evidence of type 2 inflammation and a high risk of COPD exacerbation despite the use of standard triple inhaler therapy, reducing rate of moderate or severe exacerbation and greatly improving lung function, respiratory symptoms and quality of life.
Among the patients who had a FeNO level of 20 ppb or higher at baseline, those in the dupilumab group had a greater reduction in COPD exacerbations and greater improvement in lung function than those in the placebo group. This is consistent with the known role of IL-4 and IL-13 in type 2 inflammation.
Reference:
- 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. New England Journal of Medicine. 2023;389(3):205–14. doi:10.1056/nejmoa2303951
