2024 Top Story in Respiratory Medicine: Dupilumab in COPD

Chronic obstructive pulmonary disease (COPD) is a common, chronic, progressive lung condition with high morbidity and mortality. Patients across the world are affected, and the incidence increases with age. Acute exacerbations of COPD — characterized by a worsening of cough or dyspnea, an increased volume or purulence of sputum, or a combination of these three symptoms — are known to be clinically important. They cause acute harm to the patient and are treated at great expense, but they are also important because exacerbations are known to accelerate the steady decline observed in patients with COPD.¹ In the past several years, a growth has been noted in the availability of inhaled medications to treat this chronic disease with triple-inhaled therapy (consisting of a long-acting beta agonist, a long-acting anti-muscarinic, and an inhaled glucocorticoid), which, now, is the standard of care for the most severely affected patients.^2,3

In 2023, the BOREAS group found that there was a role for dupilumab for preventing COPD exacerbations as well as stabilizing the decline in spirometry results in a subset of patients with COPD with type 2 inflammation and high eosinophil counts by targeting IL-4 and IL-13.⁴ Previous efforts to target eosinophils directly in patients with type 2 inflammation (through anti–IL-5 medications) seemed promising but failed compared with the consistent use of triple-inhaled therapy.^5,6 The NOTUS study⁷ was designed to build on these previous trials to confirm or deny the efficacy of dupilumab in the treatment of patients with COPD and type 2 inflammation who were already being managed with standard-of-care triple-inhaled therapy.

In the NOTUS trial — a phase III, double-blind, randomized trial — participants with COPD who had a blood eosinophil count of 300 cells per microliter or higher, all of whom were on triple-inhaled therapy, were assigned to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks, in addition to their standard therapy. The primary endpoint was a reduction in moderate to severe COPD exacerbations. Secondary endpoints included a change in FEV₁ over 52 weeks as well as change in the St. George's Respiratory Questionnaire (SGRQ) at the end of 1 year.

A total of 935 patients were enrolled. At the end of 52 weeks, the annualized rate of moderate or severe exacerbations was 0.86 (95% CI, 0.70–1.06) with dupilumab and 1.30 (95% CI, 1.05–1.60) with placebo; the rate ratio compared with placebo was 0.66 (95% CI, 0.54–0.82; P < .001). FEV₁ increased from baseline to week 12 with dupilumab (139 mL; 95% CI, 105–173) compared with placebo (57 mL; 95% CI, 23–91), with a significant least-squares mean difference at week 12 and week 52 (P = .02). No significant between-group difference was observed in the change in SGRQ scores over 52 weeks.

The NOTUS trial confirms the efficacy of dupilumab in reducing exacerbations in some patients with COPD and type 2 inflammation, including those well managed on triple-inhaled therapy. It should be considered in addition to standard triple-inhaled therapy in patients with COPD with high (>300 cells) eosinophil counts. Although the results are promising, several limitations must be noted. First, although COPD exacerbations decreased by 34%, there was minimal significant change in FEV₁ over time. Second, there was no difference in the other patient-centered outcome; that is, how participants felt, as measured by the SGRQ. Third, the frequency of exacerbations in the placebo group also dropped significantly from 2.1 events per year to 1.3 events per year. This might have been due to improved adherence to triple-inhaled therapy in the setting of clinical trial enrollment. In any event, had these patients showed an event rate of 1.3 exacerbations per year at the start of the trial, they would not have met the criteria for enrollment (ie, they would have been "too well").

Finally, it needs to be noted that non-White patients were greatly underrepresented in this trial. This was similar to the large triple-inhaled therapy trials (3% and 3.5% Black) as well as the anti–IL-5 trials (1.6% and 2.6% Black). The NOTUS trial included just 1.3% Black patients, with 90% of those enrolled identified as "White" and only 8% as non-White/non-Black. It is estimated that well over 75% of the world’s population is non-White. Therefore, as long as these large clinical COPD trials overrepresent a global minority group above the global majority, we will be left with a large gap in our knowledge.