Dupilumab decreases exacerbation rate, improves lung function in COPD type 2 inflammation
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Key takeaways:
- Adults with moderate or severe COPD receiving 300 mg of dupilumab every 2 weeks had a 30% lower annualized rate of exacerbations vs. placebo.
- Dupilumab also increased patients’ FEV1 and quality of life.
WASHINGTON — At 52 weeks, adults with moderate/severe COPD and type 2 inflammation receiving dupilumab had a lower exacerbation rate and better lung function, according to an American Thoracic Society International Conference presentation.
“Dupilumab reduced the annualized rate of exacerbations, moderate and severe, by 30%, compared to placebo, and also was associated with a significant improvement in lung function, quality of life and the severity of symptoms,” Surya P. Bhatt, MD, MSPH, co-first author of the study and associate professor of medicine in the division of pulmonary, allergy and critical care medicine at University of Alabama at Birmingham, said during a presentation. “The drug was safe as has been shown in several previous studies of dupilumab for other indications.”
In a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 study (BOREAS), Bhatt and colleagues analyzed 939 adults (mean age, 65.1 years; 66% men; 84.1% white) with moderate or severe COPD who were current or former smokers with type 2 inflammation to see if dupilumab reduced the annual exacerbation rate in this patient population over 52 weeks.
During a second presentation on the study, Klaus F. Rabe, MD, PhD, the other co-first author of the study and professor of pulmonary medicine at the University of Kiel, highlighted several traits that were necessary in the studied patient population including experience of at least two moderate exacerbations or at least one severe exacerbation in the year before screening, background triple therapy, symptomatic for chronic bronchitis and a blood eosinophil count of at least 300 cells/µL at screening.
In addition to evaluating the change in exacerbation rate from baseline to week 52, researchers assessed changes in lung function, St. George Respiratory Questionnaire (SGRQ) scores and Evaluating Respiratory Symptoms (E-RS):COPD scores at the end of the study period, according to the presentation.
Of the total cohort, 468 patients received 300 mg of dupilumab every 2 weeks, and 471 patients received placebo every 2 weeks. Rabe pointed out in his presentation that across both cohorts, the majority of patients were on triple therapy, with 97.2% of patients in the dupilumab group and 97.6% of patients in the placebo group receiving this type of background medication.
Compared with patients on placebo, patients on dupilumab showed a 30% decrease in annualized exacerbation rate at week 52 (1.1 vs. 0.78; P < .001), according to the presentation.
“The separation [between dupilumab and placebo] occurs relatively early, and it continues to actually parting the lines from that, suggesting that if you would continue this over the years to come, there’s no sign of symptoms that this is actually going to go down or decreasing in frequency,” Rabe said during the presentation.
When taking a closer look at this result across subgroups of patients by gender, baseline inhaled corticosteroids dose, smoking status and baseline post-bronchodilator FEV1 percent predicted, researchers found that dupilumab continued to perform better within each group.
In terms of lung function, researchers found that dupilumab improved pre-bronchodilator FEV1 by 83 mL (95% CI, 42 mL-125 mL) at 12 weeks compared with placebo, and this level of improvement was again found in the dupilumab group at 52 weeks (83 mL; 95% CI, 38 mL-128 mL), which Rabe said demonstrates early and rapid improvement.
Notably, subgroup analysis showed that dupilumab performed better within all groups when evaluating pre-bronchodilator FEV1 changes.
Patients receiving dupilumab also showed more improvement in quality of life and COPD symptoms than patients receiving placebo, Rabe said. At week 52, researchers observed a least square mean difference of –3.4 (95% CI, –5.5 to –1.3) in SGRQ scores between the groups and a least square mean difference of –1.1 (95% CI, –1.8 to –0.4) in E-RS:COPD scores. Within the three SGRQ domains that make up the total score, dupilumab resulted in more improvement in each one than placebo (activities, P = .001; impact, P = .024; symptoms, P = .012). Dupilumab also led to more improvement in the symptom domains of the E-RS:COPD score compared with placebo (breathlessness, P = .001; cough and sputum, P = .017; chest symptoms, P = .017), according to the presentation.
Lastly, researchers observed a similar number of patients who reported a treatment effect adverse event in both groups, with these types of events occurring in 76% of patients in the placebo group and 77.4% of patients in the dupilumab group.
Several of these outcomes occurred in 5% or more of both those receiving dupilumab and those receiving placebo, including nasopharyngitis, headache, upper respiratory tract infection and COPD. About 5% of patients in the dupilumab group also reported diarrhea and back pain, whereas 5% or more patients in the placebo group reported additional events of COVID-19 and hypertension.
When discussing why the New England Journal of Medicine published this trial, Darren B. Taichman, MD, PhD, chair of the session and associate director of the pulmonary vascular disease program at Penn Medicine, said there were three reasons.
“One, because it’s the first biologic agent being applied to the care of a subset of patients with COPD,” Taichman said. “Also ... it’s demonstrating in a very direct way, the involvement of type 2 inflammation in COPD.”
Lastly, this trial provided an example of “targeting treatable traits,” Taichman added.
“You're going after a phenotype, this phenotype being risk for exacerbation,” he said. “You’re identifying that according to a validated biomarker — here, increased blood eosinophils — and then based on that biomarker, you’re choosing the therapy that identifies a specific therapy aimed at the pathogenesis — here, marker of type 2 inflammation. That's very different than what we generally do, which is throw our therapies at a very generic diagnosis of COPD, assuming all these patients have the same thing, or on the basis of a far less specific measure, that being FEV1.”
Reference:
- Bhatt S. Scientific Symposium. A84. JAMA and The New England Journal of Medicine. Discussion on the edge: Reports of recently published pulmonary research. Presented at: American Thoracic Society International Conference; May 19-24, 2023; Washington, D.C.
Perspective
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This study is very significant and potentially practice changing for COPD patients, albeit for a small subgroup. While we have previously recognized that there is a subset of COPD patients that display Type II inflammation, the BOREAS study validates this knowledge due to the effects of dupilumab reducing inflammation. Prior studies looking at other anti-inflammatory targeted therapies (eg, IL-5 inhibitors and IL-5 receptor blockers) had demonstrated mixed results, but the BOREAS results could be a first step in changing the dogma of COPD treatment.
However, there are some limitations to the study, such as the majority of the patients were enrolled during the COVID-19 pandemic (a time where overall COPD exacerbations were reduced as compared with the norm), the Black population was severely underrepresented, and there was no stratification based on smoking severity. Nonetheless, the findings remain impressive and robust.
In our experience, COPD is a very heterogeneous disease that classically has been treated with a broad approach with bronchodilators and nonspecific anti-inflammatory medications. Recognizing potential subtypes of COPD and targeted therapies could help health care workers deliver better care to individuals and decrease the overall burden on the health care system. We need to recognize that not all COPD is the same.
It is important to acknowledge that this is the only study to demonstrate these findings. Although it is powered well and has few limitations, it needs replication which is the next step. A similar study, the NOTUS study, is already underway to confirm these results and will be out in 2024. Until this is published and demonstrates similar findings, it will be difficult to reliably prescribe dupilumab to patients because it does not have FDA approval for COPD.
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Rabe KF, et al. Scientific Symposium. B13. Breaking news: Clinical trial results in pulmonary medicine. Presented at: American Thoracic Society International Conference; May 19-24, 2023; Washington, D.C.
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