麻豆传媒

Among children with uncontrolled, moderate-to-severe asthma, treatment with the biologic dupilumab (Dupixent) was associated with a reduction in exacerbation and improvements in lung function in phase III findings from the international trial.

Evidence of lung function improvement occurred within 2 weeks of treatment initiation, and was sustained during the 52-week randomized, placebo-controlled trial.

Compared with the placebo group, dupilumab-treated children (ages 6 to 11 years) showed a 59% reduction in exacerbations, along with improvements in forced expiratory volume (FEV₁) and reduced airway inflammation, as measured by fractional exhaled nitric oxide (FeNO), reported VOYAGE lead researcher Leonard Bacharier, MD, of Vanderbilt University Medical Center in Nashville.

Bacharier presented findings from the pediatric study at the virtual meeting.

Dupilumab is currently approved in the U.S. for the treatment of atopic dermatitis in patients ages 6 and older, chronic rhinosinusitis with nasal polyposis in adults, and for the treatment of uncontrolled asthma with an eosinophilic- or oral steroid-dependent-phenotype in patients 12 and older.

"While asthma is a heterogeneous disease, the most common driver of asthma in children is type 2 inflammation characterized by the release of signature cytokines, such as interleukin (IL)-4, IL-5, and IL-13," Bacharier said.

He noted that dupilumab is a fully human monoclonal antibody that blocks the shared receptor component of IL-4 and IL-13, thereby inhibiting their signaling.

"These cytokines are key and central drivers of type 2 inflammation in diseases such as atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps and eosinophilic esophagitis," he said.

The study included children ages 6 to 11 randomized 2:1 to receive subcutaneous dupilumab 100 mg (body weight ≤ 30 kg) or 200 mg (body weight >30 kg) every 2 weeks, or matched placebo.

The study included mostly children with type 2 inflammatory phenotype (baseline blood eosinophil ≥150 cells/μL or FeNO≥20 ppb) and/or baseline blood eosinophils ≥300 cells/μL.

The primary endpoint was annualized rate of severe asthma exacerbation change from baseline in pre-bronchodilator FEV₁ percent predicted (FEV_1pp). Secondary endpoints were FeNO level at week 12 and change in Asthma Control Questionnaire-Interviewer Administered (ACQ-7-1A) at week 24.

After the treatment period, participants had the opportunity to enroll in an open-label extension.

Of the 408 patients enrolled in the study, 350 had the type 2 phenotype and 259 had baseline blood eosinophils ≥300 cells/μL. Baseline characteristics of the two treatment groups were similar.

Among the main study findings:

• Treatment with dupilumab was associated with a 59.3% (P<0.0001) reduction in exacerbation rate among children with the type 2 phenotype and improved FEV_1pp (least squares [LS] mean difference vs placebo 5.21%; P=0.0009)

• In this population, dupilumab treatment was also associated with a reduction in FeNO levels (LS mean difference vs placebo of -17.84; P<0.0001) at week 12 compared with placebo

• At week 24, dupilumab-treated patients showed greater improvement in ACQ-7-1A scores from baseline versus placebo (LS mean difference vs placebo of -0.33, P=0.0001)

• The findings were similar in patients with eosinophilic (≥300 cell/μL) asthma, with a 65% reduction in the annualized rate of severe exacerbations versus placebo reported in this population

"Looking at changes over time, we can see that dupilumab resulted in rapid changes in the percentage of predicted pre-bronchodilator FEV₁," Bacharier said. "In both primary efficacy populations, the benefit of dupilumab over placebo was apparent from the first measurement at week 2. In the type 2 phenotype population the initial improvement over baseline plateaued at 10% points from baseline at week 12 and remained sustained up to 52 weeks, compared to the 5% change in the placebo population."

The overall rates of treatment-emergent adverse events in the dupilumab and placebo groups were 83% and 80%, respectively, with 4.8% of dupilumab-treatment patients and 4.5% of placebo-treated patients reporting serious adverse events.

A total of 1.8% and 1.5% of dupilumab- and placebo-treated patients, respectively, reported adverse events leading to study discontinuation.

Following his presentation, in response to a question about whether the lung function improvement seen in the study was clinically relevant, Bacharier said the response was similar to that seen in other trials in adults and adolescents.

"We are confident that this degree of lung function improvement reflects a clinically relevant improvement," he said.

He acknowledged that lack of minority representation was a study limitation. The average patient age was 9 years, two-thirds of the participants were male, and more than 80% were white.

Session co-moderator Jennifer Taylor-Cousar, MD, of National Jewish Health in Denver, noted that the higher asthma rate among Black children compared with that of White children.

"This really speaks to the international nature of this trial, and I think it is one of the areas where future studies are going to have to help us identify the generalizability across race and ethnicity of these therapies," Bacharier said.

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