The second phase III trial from NOTUS study investigators, led by Surya P. Bhatt, MD, MSH, of the University of Alabama at Birmingham, was published in the New England Journal of Medicine.
Dupilumab blocks the shared receptor component for interleukin-4 and interleukin-13. Key and central drivers of type 2 inflammation and was shown to be effective and safe in an earlier phase III trial involving patients with COPD, type 2 inflammation, and an elevated risk of exacerbation.
For the current phase III, double-blind, randomized trial, the study team assigned patients with COPD who had a blood eosinophil count of 300 cells/µL or higher to receive SC dupilumab (300 mg) or placebo every 2 weeks. The primary end point was defined as the annualized rate of moderate or severe exacerbations, while key secondary end points were any changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV1) at Weeks 12 and 52 and in the St. George’s Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at Week 52.
Of the 935 patients who underwent randomization, 470 were assigned to the dupilumab group and 465 to the placebo group. The primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at Week 52.
The results indicated that the annualized rate of moderate or severe exacerbations was 0.86 (95% CI, 0.70-1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P <.001).
The researchers reported that the prebronchodilator FEV1 increased from baseline to Week 12 with dupilumab (least-squares mean change, 139 mL [95% CI, 105-173]) compared with placebo (least-squares mean change, 57 mL [95% CI, 23-91]), with a significant least-squares mean difference at week 12 of 82 mL (P <.001) and at Week 52 of 62 mL (P = .02).
The researchers added that no significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. In addition, the incidence of adverse events was similar in the two groups and consistent with previous findings.
“In patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo,” according to the industry-funded study.
The researchers pointed out that about one-half of patients with COPD continue to have exacerbations despite maximal standard care with inhaled triple therapy consisting of a glucocorticoid agent, a long-acting muscarinic antagonist (LAMA), and a long-acting β-agonist (LABA), adding, “Thus, prevention of exacerbations is an important goal for new COPD therapeutics, alongside improvement in lung function and health-related quality of life.”
The study team explained that a subgroup of COPD patients shows evidence of local and systemic type 2 inflammation, which is regulated by type 2 helper T-cells and innate lymphoid cells and driven by inflammatory cytokines, including interleukin (IL)-4, IL-5, and IL-13.
Dupilumab blocks the IL-4 and IL-13 pathways and is approved for multiple diseases involving type 2 inflammation. That raised the possibility that it could be effective therapy in patients with COPD characterized by type 2 inflammation and led to the study.
In the previous phase III trial, dupilumab was found to be effective in treating patients with COPD and type 2 inflammation. Specifically, it was associated with a reduction in moderate or severe exacerbations, improvements in lung function and patient-reported health-related quality of life, and a lessening of the severity of symptoms. The more recent NOTUS trial sought to confirm the efficacy and safety of dupilumab in patients with COPD and evidence of type 2 inflammation indicated by blood eosinophil count and high exacerbation risk despite the use of inhaled triple therapy.
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