乌鸦传媒

SAN DIEGO -- Two trials showed the anti-interleukin-4/13 drug dupilumab (Dupixent) was associated with significantly lower exacerbation rates, better lung function and and improved asthma control, compared to placebo, in patients with moderate-to severe uncontrolled asthma.

In the year-long QUEST clinical trial, patients treated every two weeks with injections of dupilumab showed a roughly 48% reduction in exacerbations, compared to patients given placebo injections.

In the related VENTURE trial, which enrolled patients with glucocorticoid-dependent severe asthma, treatment with dupilumab was associated with reduced oral steroid use, fewer exacerbations and increased lung function (as measured by FEV₁) compared to placebo.

Results from the trials were reported at ATS 2018 - the international meeting of the American Thoracic Society - in conjunction with publication in the New England Journal of Medicine.

The to market dupilumab as a treatment for moderate-to-severe, uncontrolled asthma. The biologic received FDA approval in the spring of 2017 to treat moderate-to-severe atopic dermatitis not adequately controlled with topical prescription therapies.

Dupilumab targets the IL-4 receptor's alpha subunit, blocking both IL-4 and IL-13 signalling.

QUEST

In an interview with 乌鸦传媒, QUEST lead researcher Mario Castro, MD, of Washington University in St. Louis, Missouri, characterized the improvement in lung function experienced by some dupilumab-treated patients as "dramatic."

"This treatment targets patients with type 2 inflammation driven by cytokines 4, 5, and 13," he said, adding that this represents about 50% of patients with severe asthma.

The 52-week QUEST study included 1,902 patients with uncontrolled asthma randomized to receive subcutaneous dupilumab as an add-on therapy at doses of 200 mg or 300 mg every two weeks, or matched-volume placebo injections.

Primary endpoints included annualized severe exacerbation rate and absolute change from baseline to week 12 in forced expiratory volume in 1 second (FEV₁) before bronchodilator use. Secondary endpoints included exacerbation rate and FEV₁ in patients with blood eosinophil counts of ≥300.

Among the main study findings:

• The annualized rate of severe asthma exacerbations was 0.46 (95% CI 0.39-0.53) among patients receiving 200 mg of dupilumab every two weeks and 0.87 (95% CI, 0.72-1.05) among patients receiving placebo injections, for a 47.7% lower rate with dupilumab (P<0.001). Patients treated with 300 mg biweekly injections of dupilumab showed similar outcomes.
• FEV₁ increased by 0.32 liters at 12 weeks among patients assigned to the lower dose of dupilumab (difference vs matched placebo, 0.14 liters; P<0.001). Similar results were seen with the higher dose.
• Among patients with eosinophilic asthma, the annualized rate of severe asthma exacerbations was 0.37 (95% CI 0.29-0.48) among those receiving the lower dose of dupilumab and 1.08 (95% CI 0.85-1.38) among those receiving placebo (65.8% lower rate with dupilumab).

Blood eosinophilia at the beginning of treatment occurred in 52 patients (4.1%) receiving dupilumab versus 4 patients (0.6%) in the placebo arm of the study.

VENTURE

The VENTURE study, designed to assess whether treatment with the monoclonal antibody would allow patients with severe asthma to reduce oral glucocorticoid doses and remain in control, included 210 patients randomized to receive add-on dupilumab (300 mg) or placebo every two weeks for 24 weeks.

After a glucocorticoid-adjustment period before randomization, steroid doses were adjusted downward from week 4 to week 20 and then maintained at a stable dose for four weeks.

The primary endpoint was percentage reduction in glucocorticoid dose at week 24, and secondary endpoints included the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day.

Among the main findings:

• The percentage change in the glucocorticoid dose was -70.1% in the dupilumab group, compared to -41.9% in the placebo group (P<0.001), with 80% vs. 50% of dupilumab patients having steroid dose reductions of at least 50%.
• 69% of dupilumab patients versus 33% of placebo patients had dose reductions to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoids.
• The severe exacerbation rate was 59% lower in the dupilumab patients (95% CI 37%-74%), despite reductions in glucocorticoid dosing, resulting in an FEV₁ that was 0.22 liters (95% CI 00.9-0.34) higher.

Just over twice as many patients on dupilumab experienced injection site reactions (9% vs 4%), and transient blood eosinophilia was seen in 14% of dupilumab-treated patients versus 1% of placebo-treated patients.

In a late breaking research session held Monday at ATS 2018, lead researcher Klaus Rabe, MD, of the LungClinic Grosshansdorf in Germany, said the eosinophilia in the dupilumab patients was detected in laboratory findings and was unrelated to clinical outcomes.

"This drug is effective for eosinophil trafficking, but it did not result in the release of eosinophils at the level where it would make people symptomatic," he said.

Rabe noted that the biologic's efficacy seems to be independent of the classical biomarkers such as eosinophilia.

"This medication appears to have efficacy in a much broader range of patients than the currently available biologics," pulmonologist Sally Wenzel, MD, of the University of Pittsburgh told 乌鸦传媒.

"It has the potential to be a game changer for some patients, but we won't really know until it is out in the real world."

Wenzel said because dupilumab is so expensive -- as much as $3,000 per injection or $37,000 a year -- identifying patients who really need it will be critical.

"For patients who have a lot of comorbidities, and are missing a lot of work or school, it has the potential to be cost effective," she said.