The biologic agent dupilumab can improve asthma control and help wean patients with severe asthma from chronic oral steroids, according to findings of two recent studies published in The New England Journal of Medicine. Dupilumab is currently approved to treat moderate-to-severe eczema in adults.
"I have patients who have had to stop working and go on disability because their asthma symptoms are so severe they can no longer function in the workplace," said study author Mario Castro, MD, the Washington University School of Medicine, St. Louis, MO. "I'm excited about the potential of dupilumab because I have so many patients who have maxed out on available therapies and they still can't breathe. It can become a very disabling disease.”
About half of all patients with asthma are affected by type 2 inflammation, which is mediated by cytokines including interleukin (IL)-4, IL-5, and IL-13. Dupilumab is a monoclonal antibody that targets the alpha-subunit of IL-4 and blocks IL-4 and IL-13 signaling, and thus type 2 inflammation.
In this phase 3, randomized, double-blind, placebo-controlled, parallel-group trial trial—called Liberty Asthma Quest—researchers examined the safety and efficacy of dupilumab in patients aged 12 years and older with persistent asthma. In total, 1,902 patients were randomized to the following groups in a 2:2:1:1 ratio, respectively:
- Add-on subcutaneous dupilumab 200 mg every 2 weeks
- Add-on subcutaneous dupilumab 300 mg every 2 weeks
- Matched-volume placebo to 200 mg every 2 weeks
- Matched-volume placebo to 300 mg every 2 weeks
“Patients completed a screening period of 4 weeks (window: ±1 week), followed by randomization to subcutaneous injections of dupilumab or matched-volume placebo, a 52-week randomized intervention period, and a 12-week postintervention follow-up period,” wrote the authors.
The researchers’ primary endpoints were annual rates of severe asthma exacerbation and the change in FEV1 between baseline and week 12. Secondary endpoints were exacerbation rates and FEV1 in patients with blood eosinophil counts >300/mm3. The researchers also determined asthma control and dupilumab safety.
The annual rate of severe asthma exacerbations in those receiving dupilumab 200 mg was 0.46 (95% CI: 0.39-0.53) compared with that of 0.87 (95% CI: 0.72-1.05) in those receiving matched placebo, reflecting a 47.7% lower rate of exacerbations with dupilumab. Furthermore, FEV1 increased by 0.32 L by week 12 in patients receiving dupilumab 200 mg. Similar results were observed in the higher dose dupilumab experimental group.
Notably, the researchers observed even bigger beneficial effects in patients with higher eosinophil counts, an indicator of type 2 inflammation.
The team also found that dupilumab may play a role in airway remodeling based on analysis of postbronchial FEV1 slope. Dr. Castro and colleagues also validated that IL-4 and IL-13 play key roles in type 2 inflammation based on biomarkers such as IgE and FeNO.
“We found that dupilumab effectively treated patients with moderate-to-severe asthma, providing a significant reduction in the rate of severe exacerbations, rapid and sustained improvement in lung function and asthma control, and symptom relief,” the researchers wrote. “The most robust results were observed in patients with elevated type 2 immune characteristics, including eosinophil counts and FeNO.”
The frequency of negative side effects was comparable across experimental and control groups, with the most frequent adverse event being injection-site reaction, most commonly seen in patients receiving dupilumab. Furthermore, transient blood eosinophilia was more common in the experimental group as compared with that of the control group.
In another study, titled Liberty Asthma Venture, researchers compared the safety and efficacy of dupilumab vs placebo in decreasing the maintenance dosages of oral steroids in 210 patients with oral-glucocorticoid-treated asthma aged 12 years and older.
Patients were randomized in a 1:1 ratio to receive either add-on dupilumab (300 mg) or placebo every 2 weeks for 24 weeks. The researchers tapered glucocorticoid doses between week 4 and week 20, and then held patients at a steady dose for 4 weeks, following a glucocorticoid dose-adjustment period before randomization.
The researchers’ primary endpoint was the percentage reduction in the glucocorticoid dose at week 24, with secondary endpoints being the number of patients at week 24 with a decrease of at least 50% in the glucocorticoid dose and those with a decrease in glucocorticoid dose to fewer than 5 mg/day. The team also analyzed exacerbation rates and FEV1.
“The percentage change in the glucocorticoid dose was −70.1% in the dupilumab group, as compared with −41.9% in the placebo group (P < 0.001); 80% vs 50% of the patients had a dose reduction of at least 50%, 69% vs 33% had a dose reduction to less than 5 mg/day, and 48% vs 25% completely discontinued oral glucocorticoid use,” wrote primary author Klaus F. Rabe, MD, PhD, LungenClinic Grosshansdorf, and Christian Albrechts University Kiel, Germany.
Dr. Rabe and colleagues also found that dupilumab use led to a 59% drop in exacerbation rates (95% CI: 37-74), as well as a boost to FEV1 in these patients by 0.22 L (95% CI: 0.09-0.34)—even with steroid weaning. Of note, injection site reactions and transient blood eosinophilia were more common in the experimental group.
As with the Liberty Asthma Quest, the beneficial effects of dupilumab in the Liberty Asthma Venture trial were most pronounced in patients with higher levels of type 2 inflammation.
The team attributes the reduction in oral glucocorticoid doses observed in the placebo group to improved drug adherence during the trial.
“Add-on therapy with dupilumab significantly reduced the oral glucocorticoid dose while simultaneously reducing the rate of severe exacerbations and improving lung function (FEV1) in patients with glucocorticoid-dependent severe asthma,” the researchers wrote.
Dr. Castro added: "This drug not only reduced severe symptoms of asthma, it improved the ability to breathe. That's important because these patients have a chronic disabling disease that worsens over time with loss of lung function. So far, we do not have a drug for asthma that changes the course of the disease. Current drugs for severe asthma help reduce trips to the emergency room, for example, but they don't improve lung function."