Dupilumab lowers exacerbations, betters lung function in COPD with type 2 inflammation

Key takeaways:

• At 52 weeks, patients receiving dupilumab vs. placebo had improved measures of quality of life and symptom burden.
• Through this study, researchers have confirmed findings from the BOREAS study.

SAN DIEGO — With dupilumab vs. placebo, adults with moderate to severe COPD and type 2 inflammation experienced fewer exacerbations, according to research presented at the American Thoracic Society International Conference.

These data were simultaneously published in The New England Journal of Medicine.

As Healio previously reported, adults with moderate/severe COPD and type 2 inflammation receiving dupilumab (Dupixent; Regeneron, Sanofi) had a lower exacerbation rate and better lung function at 52 weeks in the phase 3 BOREAS trial presented at last year’s ATS meeting.

“Exacerbations of COPD have a substantial impact on short-term morbidity, but also on long-term outcomes for these patients, including disease progression and in some cases death,” Surya P. Bhatt, MD, MSPH, professor in the division of pulmonary, allergy and critical care medicine at The University of Alabama at Birmingham, told Healio. “By decreasing exacerbations, the hope is that we can decrease the rate of progression of the disease.”

In the multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 NOTUS study, Bhatt and colleagues assessed 935 current/former smokers (mean age, 65 years; 67.6% men; 89.6% white; 32.1% Hispanic/Latino) with moderate to severe COPD and type 2 inflammation (blood eosinophil count ≥ 300 cells/μL) primarily receiving background and stable triple therapy to determine the impact of 300 mg dupilumab subcutaneously every 2 weeks vs. placebo on moderate to severe exacerbations at week 52.

“Exacerbations are not without consequence. They often lead to faster progression of the disease in the form of lung function decline, emphysema progression and sometimes even mortality,” Bhatt said during his presentation. “Prevention of these exacerbations is a really important unmet need and an important target for new therapeutics.”

Researchers also evaluated drug safety and prebronchodilator FEV₁, St. George’s Respiratory Questionnaire (SGRQ) total score and Evaluating Respiratory Symptoms in COPD (E-RS: COPD) total score at week 52 of treatment vs. baseline in the two groups.

During his presentation, Bhatt specifically highlighted that patients aged up to 85 years could participate in this study. In the BOREAS study, the maximum age was 80 years.

In the year before the study, patients experienced a minimum of two moderate exacerbations or a minimum of one severe exacerbation. Included patients also were classified as “highly symptomatic,” Bhatt said during the presentation.

“They had to have an MRC dyspnea score of at least one, which is basically shortness of breath while hurriedly walking or walking slightly uphill, and they also had to have chronic bronchitis, which in this study was defined as cough and mucus production for at least 3 months in the previous year,” Bhatt said.

At randomization, 470 patients (mean age, 65.2 years; 68.1% men; 89.8% white; 32.1% Hispanic/Latino) received dupilumab, and 465 patients (mean age, 64.9 years; 67.1% men; 89.5% white; 32% Hispanic/Latino) received placebo.

Within the total study population, the average blood eosinophil count was 407 cells/μL, and 30.4% (n = 284) of patients had emphysema. Bhatt noted that a similar proportion of patients in the dupilumab group and the placebo group had emphysema.

Findings

Healio previously reported on topline results from this phase 3 trial back in November 2023.

At the 52-week mark, patients receiving dupilumab vs. placebo had a decrease in the annualized rate of moderate or severe exacerbations by 34% (P < .001), and Bhatt noted in his presentation that this result was adjusted for smoking status, number of previous exacerbations and disease severity.

In terms of time to first moderate/severe exacerbation, researchers observed a lower probability for this outcome in the dupilumab group (HR = 0.71; 95% CI, 0.57-0.89).

To analyze whether the observed annualized rate of exacerbations varied based on gender, smoking status, baseline predicted postbronchodilator FEV₁, history of emphysema and baseline eosinophil counts, researchers divided the cohort into these subgroups.

Across all subgroups, dupilumab was shown to be better than placebo, and exacerbation reduction did not greatly differ within any of the assessed subgroups.

“Even if you have variability in eosinophil counts over a short period of time, you’re still very likely to respond,” Bhatt said.

Between baseline and week 12, researchers observed a larger positive change in prebronchodilator FEV₁ in the dupilumab group vs. the placebo group (least-squares mean difference, 82 mL; 95% CI, 33-131). The same was true when evaluating changes between baseline and week 52, with a larger change observed among those receiving dupilumab (least-squares mean difference, 62 mL; 95% CI, 11-113).

Researchers again found that dupilumab was better than placebo across all subgroups, and week 12 changes in prebronchodilator FEV₁ did not greatly differ within these groups.

By week 52, baseline SGRQ scores signaling quality of life improved to a greater degree among those receiving dupilumab vs. placebo (least-squares mean difference, –3.4 points; 95% CI, –5.8 to –0.9). Bhatt further noted that this finding was true across the three domains of the SGRQ: activity, impact and symptoms.

The dupilumab group also had larger improvements in the E-RS: COPD total score representing symptom burden at week 52 vs. the placebo group (least-squares mean difference, –0.6; 95% CI, –1.4 to 0.2).

In terms of nitric oxide levels, Bhatt highlighted that dupilumab reduced this level more than placebo over 52 weeks, whereas “there was no change in the blood eosinophils.”

Both groups had comparable rates of treatment-emergent adverse events (dupilumab, 66.7% vs. placebo, 65.9%).

“[The two groups] were well balanced, so there is no safety concern in the study,” Bhatt said during his presentation.

According to the presentation, more patients receiving dupilumab vs. placebo experienced COVID-19 (9.4% vs. 8.2%), nasopharyngitis (6.2% vs. 5.2%) and headache (7.5% vs. 6.5%), whereas more patients receiving placebo experienced COPD exacerbations (7.8% vs. 4.9%).

Slightly more patients in the placebo vs. dupilumab group also experienced a major adverse cardiovascular event (n = 7 vs. n = 3).

Additionally, Bhatt said the number of deaths due to an adverse event were similar in the dupilumab and placebo group (n = 12 vs. n = 7).

“There’s a lot of interest right now in testing dupilumab and other biologics as potential disease modifiers,” Bhatt told Healio. “Whether they can alter disease progression in the form of lung function decline or progression of structural lung disease, that remains to be tested.

“There are several phase 3 clinical trials of biologics that are scheduled to read out in the next year,” Bhatt added. “I think we may soon be in a period where we will potentially have the option to find the right biologic for the right patient and have a variety of options to pick from. That will be an exciting phase for COPD patients.”

Notably, the FDA granted priority review to dupilumab to treat adults with uncontrolled COPD with type 2 inflammation, in part, on data from BOREAS and NOTUS back in February.

A Sanofi press release notes that the target action date for the drug is June 27.

“Approval of dupilumab will mean that a new drug is available after a very long time for patients who undergo frequent exacerbations who now have very limited treatment options,” Bhatt told Healio.

References:

• Bhatt SP, et al. N Eng J Med. 2024;doi:10.1056/NEJMoa2401304.
• Dupixent late-breaking data from NOTUS confirmatory phase 2 COPD study presented at ATS and published in NEJM. https://www.news.sanofi.us/2024-05-20-Dupixent-R-late-breaking-data-from-NOTUS-confirmatory-phase-3-COPD-study-presented-at-ATS-and-published-in-NEJM. Published May 20, 2024. Accessed May 20, 2024.