番茄社区

SAN DIEGO -- Adding dupilumab (Dupixent) to triple therapy reduced exacerbations and improved lung function for chronic obstructive pulmonary disease (COPD) patients with blood eosinophil evidence of type 2 inflammation, a second phase III trial demonstrated.

Among COPD patients already on maximum inhaled therapy, the biologic reduced moderate or severe exacerbations by 34%, with annualized rates dropping from 1.30 for those assigned to placebo to 0.86 among dupilumab recipients (rate ratio 0.66, 95% CI 0.54-0.82, P<0.001), Surya Bhatt, MD, MSPH, of the University of Alabama at Birmingham, reported here at the American Thoracic Society (ATS) annual meeting.

In addition, dupilumab led to better lung function, as shown by improvements in forced expiratory volume in 1 second (FEV₁), while adverse event (AE) rates were similar between the two study arms, according to findings of the so-called NOTUS trial, which were simultaneously published in the .

About half of COPD patients despite using inhaled triple therapy -- a combination of a glucocorticoid agent, a long-acting muscarinic antagonist (LAMA), and a long-acting beta-agonist (LABA).

"These exacerbations are not without consequence," Bhatt explained during his presentation. "They often lead to faster progression of the disease in normal lung function decline, emphysema progression, and sometimes even mortality."

The findings from NOTUS confirm those of BOREAS, presented at last year's ATS meeting, which also demonstrated the effectiveness of the subcutaneous interleukin (IL)-4/IL-13-targeted agent in lowering exacerbation rates and improving lung function in this patient population.

Already indicated for asthma and eosinophilic esophagitis, among other conditions, the two phase III trials set the stage for dupilumab to become the first biologic approved for COPD. An FDA decision is expected by the end of June, . Approximately 20% of COPD patients have type 2 inflammation, as indicated by blood eosinophil counts.

"This kind of treatment can help target different patients with this specific endotype," Bhatt told 番茄社区, adding that there's "a huge unmet need" for COPD patients who experience frequent exacerbations despite maximum inhaled therapy.

The 52-week phase III was conducted across 329 sites in 29 countries, with a total of 935 COPD patients with type 2 inflammation randomized 1:1 to either subcutaneous dupilumab (300 mg) or matching placebo every 2 weeks on top of their current inhaler therapy. The primary analysis was performed after a positive interim analysis, with 721 participants having sufficient data.

For inclusion, participants needed to have a minimum blood eosinophil count of 300 cells/μl on at least one analysis during screening; be between the ages of 40 and 85 years; be on triple therapy or LAMA-LABA (if inhaled glucocorticoids were contraindicated); and to have experienced two or more moderate exacerbations or one severe exacerbation in the year prior to enrollment.

All patients were current or former smokers, but investigators capped enrollment for current smokers at 30%. They were also required to have a post-bronchodilator ratio of FEV₁ to the forced vital capacity (FVC) of less than 0.70 and a post-bronchodilator FEV₁ of more than 30% and up to 70% of the predicted normal value. Patients were excluded if they had asthma or another notable pulmonary disease.

Among the 935 patients randomized (two-thirds men, mean age 65 years), white patients made up the vast majority (90%), followed by American Indian or Alaska Native (5%), Asian (1%), and Black (1%) patients. About a third of participants were Hispanic or Latino. Most (71%) were former smokers (average 40 pack-year history), and 30% had emphysema.

Nearly all (99%) the patients were using inhaled triple therapy as part of their background medication, while 28% utilized an inhaled high-dose glucocorticoid.

Average blood eosinophil count at the time of randomization was 407 cells/μl, with 40% of patients below 300 cells/μl, while baseline mean pre-bronchodilator FEV₁ was 1.36 liters.

For secondary endpoint, the study showed that dupilumab led to significant improvements in pre-bronchodilator FEV₁ from baseline, with a least-squares mean change of 139 ml versus 57 ml with placebo at 12 weeks (P<0.001) and 115 ml versus 54 ml at 52 weeks (P=0.02). Among the 42% of patients who had fractional exhaled nitric oxide (FeNO) levels of 20 ppb or higher, dupilumab led to improvements in pre-bronchodilator FEV₁ at 12 weeks only (least-squares mean change of 221 ml versus 81 ml, P=0.001).

There were no significant between-group differences from baseline to 52 weeks in St. George's Respiratory Questionnaire scores or in the Evaluating Respiratory Symptoms in COPD total score.

Bhatt said the safety of dupilumab was in line with the drug's known safety profile, with AE rates of 66.7% versus 65.9% with placebo. Common AEs (5% or more patients) included COVID infection, headache, COPD, and nasopharyngitis.

Serious AEs were observed in 13% of the dupilumab group and 15.9% of the placebo group, while AEs leading to discontinuation occurred in 3.8% and 2.6%, respectively. AEs resulting in death occurred in 2.6% of the dupilumab group and 1.5% of the placebo group.

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