Dupilumab Safe, Efficacious as Steroid Replacement in Uncontrolled Asthma
JULY 06, 2018
Kenneth Bender, PharmD, MA
Mario Castro, MDTwo concurrently published studies with dupilumab (Dupixent) have evidenced its efficacy and safety in moderate-to-severe uncontrolled asthma, and in reducing steroid requirement in previously glucocorticoid-dependent severe asthma.
The results come as a great benefit to the clinical community, as approximately 20% of patients with asthma have uncontrolled, moderate-to-severe symptoms that include recurrent exacerbations. This is in spite of that maximized controller therapy is accessible to such patients, lead researcher Mario Castro, MD, professor of pulmonary and critical care medicine, Washington University School of Medicine in St. Louis, noted in the study.
With type 2 inflammation, mediated by cytokines such as interleukin-4, -5, and -13, identified in approximately 50% of patients with asthma, Castro and colleagues sought to confirm earlier indications that dupilumab—an interleukin-4 and -13 blocker previously approved to treat atopic dermatitis—could be safely added to standard, but unsuccessful treatment regimens to gain control of symptoms in moderate to severe asthma.
In a year-long, randomized controlled trial involving more than 1900 patients at least 12 years of age with uncontrolled moderate-to-severe asthma, 2 different doses of dupilumab were tested against placebo on reducing annualized rate of severe asthma exacerbation. Additional measures included the absolute change of forced expiatory volume in 1 second (FEV1) from baseline to 12 weeks.
Patients were randomly assigned in a 2:2:1:1 ratio to receive add-on therapy with dupilumab, administered subcutaneously in doses of 200 mg or 300 mg every 2 weeks after initial loading doses or matched volume placebos. Biomarkers of type-2 inflammation were measured, including blood eosinophils, fraction of exhaled nitric oxide (FENO) and serum IgE.
Castro and colleagues reported that patients treated with 200mg dupilumab had almost half the annualized rate of severe asthma exacerbations than those receiving placebo, 0.46 (95% CI; 0.39-0.53) compared to 0.87 (95% CI; 0.72-1.05). They noted similar results with the 300mg dose of dupilumab.
Dupilumab was also associated with an FEV1 increase of 0.32 liter at 12 weeks, compared to 0.14 liter increase with placebo. In the patients with blood eosinophil counts of at least 300/mm3, the annualized rate of severe asthma exacerbations was 0.37 (95% CI; 0.29-0.48) with the lower dose of dupilumab compared to 1.08 (95% CI; 0.85-1.38) with placebo.
While noting that the greatest benefit of the active drug relative to placebo was observed in patients with elevated type 2 biomarkers, Castro and colleagues also reported that blood eosinophilia occurred as an adverse treatment event, after starting the intervention, in 4.1% of those receiving dupilumab, compared to 0.6% of those on placebo.
In the companion study in 210 patients with glucocorticoid-dependent severe asthma, Klaus F. Rabe, MD, PhD, professor of pulmonary medicine, University of Kiel, and colleagues found that glucocorticoid dose was able to be substantially reduced with dupilumab compared to placebo.
They reported a 70.1% glucocorticoid dose reduction with dupilumab 300 mg every 2 weeks for 24 weeks compared to a 41.9% reduction in the placebo group. Eighty percent of those receiving dupilumab had a dose reduction of at least 50%, compared to 33% of those receiving placebo. Further, 48% of the dupilumab group were able to discontinue oral glucocorticoid use, compared to 25% of those on placebo.
Treatment-emergent blood eosinophilia was also associated with active treatment in this study, in 14% of those receiving dupilumab compared to 1% of those on placebo.
“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,” Rabe and researchers concluded.
The study, "Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma," was published online in The New England Journal of Medicine last week.