Dupilumab cuts steroid use, improves lung function in severe asthma
Dupilumab, the fully human anti-interleukin-4 receptor α monoclonal antibody indicated for the treatment of atopic dermatitis, appeared to improve lung function, reduce exacerbations, and decrease oral corticosteroid use in individuals with moderate-to-severe asthma, according to two phase III trials presented at ATS 2018.
In the LIBERTY ASTHMA QUEST* trial, 1,902 individuals (mean age 47.9 years, 62.9 percent female, mean baseline prebronchodilator FEV1** 1.78 L) with uncontrolled, persistent, moderate-to-severe asthma (on moderate-to-high dose inhaled corticosteroids plus up to two additional treatments) were randomized to receive add-on subcutaneous dupilumab (200 or 300 mg Q2W after loading doses of 400 and 600 mg, respectively; n=631 and 633, respectively) or corresponding placebos (n=638) for 52 weeks.
The annualized severe asthma exacerbation rate was 47.7 percent lower among patients on dupilumab 200 mg compared with placebo (0.46 vs 0.87; p<0.001) and 46.0 percent lower among patients on dupilumab 300 mg compared with placebo (0.52 vs 0.97; p<0.001). [N Engl J Med 2018;doi:10.1056/NEJMoa1804092; ATS 2018, abstract A6163]
At 12 weeks, dupilumab recipients also had greater increases from baseline in prebronchodilator FEV1 compared with those on placebo (difference, 0.14 and 0.13 L with dupilumab 200 and 300 mg, respectively; p<0.001 for each vs placebo).
The impact on severe asthma exacerbations appeared to be greatest in patients with higher baseline blood eosinophil counts (≥300/mm3) with a 65.8 and 67.4 percent lower rate of exacerbations with dupilumab 200 and 300 mg, respectively, over placebo (annualized rate of 0.37 vs 1.08 in patients on dupilumab 200 mg vs placebo and 0.40 vs 1.24 in patients on dupilumab 300 mg vs placebo). Similar findings were demonstrated pertaining to change from baseline in prebronchodilator FEV1 at 12 weeks (difference, 0.21 and 0.24 L for dupilumab 200 mg and 300 mg vs placebo).
The improvements in FEV1 were also was also greater among patients with higher FENO*** levels with differences of 0.30 and 0.39 L with dupilumab 200 and 300 mg vs placebo in patients with FENO ≥50 ppb.
The improvements in FEV1 with dupilumab were evident as early as week 2 and were sustained throughout the 52-week treatment period, said study lead author Professor Mario Castro from Washington University School of Medicine in St Louis, Missouri, US.
Adverse event incidence was similar between dupilumab and placebo recipients (81.0 percent vs 83.1 percent). Injection-site reactions occurred more frequently in dupilumab than placebo recipients (15.2 and 18.4 percent of patients on dupilumab 200 and 300 mg, respectively, vs 5.4 and 10.3 percent in each corresponding placebo group). Blood eosinophilia was also more common among dupilumab vs placebo recipients (4.1 percent vs 0.6 percent), leading to permanent study drug discontinuation in seven patients on dupilumab and one on placebo.
“This drug not only reduced severe symptoms of asthma, it improved the ability to breathe,” said Castro. “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,” he said.
Reduced reliance on steroids
In the LIBERTY ASTHMA VENTURE# trial, following a 3–10-week oral glucocorticoid dose-adjustment period, 210 patients (mean age 51.3 years, 40 percent male, prebronchodilator FEV1 at baseline 1.58 L) who were on long-term (≥6 months) daily systemic glucocorticoids for severe, persistent asthma (≥12 months) were randomized to receive subcutaneous dupilumab (300 mg, loading dose of 600 mg on day 1; n=103) or placebo (n=107) Q2W as add-on therapy for 24 weeks. During the trial period, glucocorticoid dose was as follows: 4 weeks on adjusted dose, 16 weeks of dose reduction every 4 weeks, and 4 weeks of maintenance on final dose.
Over the 24-week period, patients on dupilumab experienced a significant reduction in glucocorticoid dose compared with those on placebo (-70.1 percent vs -41.9 percent; p<0.001), with 80 percent of dupilumab recipients (vs 50 percent of placebo recipients) having a ≥50 percent dose reduction (odds ratio [OR], 3.98; p<0.001) and 69 percent vs 33 percent having a dose reduction to <5 mg/day (OR, 4.48; p<0.001). At week 24, 48 percent of patients on dupilumab were no longer using oral glucocorticoids compared with 25 percent of patients on placebo (p=0.002). [N Engl J Med 2018;doi:10.1056/NEJMoa1804093; ATS 2018, abstract A7712]
Despite the reduction in glucocorticoid dose, dupilumab recipients also experienced a 59 percent reduction in the rate of severe exacerbations compared with placebo recipients, and had a mean 0.22 L higher FEV1, with the greatest impact derived by patients with higher baseline blood eosinophil counts.
As with the QUEST trial, adverse event incidence was comparable between dupilumab and placebo recipients (62 percent vs 64 percent). Injection-site reactions occurred more frequently in dupilumab compared with placebo recipients (9 percent vs 4 percent), as did transient eosinophilia (14 percent vs 1 percent) and sinusitis (7 percent vs 4 percent), while viral upper respiratory tract infections (9 percent vs 18 percent) and influenza (3 percent vs 6 percent) were more common in placebo recipients.
While many patients with severe asthma require systemic corticosteroid therapy, these treatments are associated with toxic effects. This leaves a role for additional therapies that could potentially reduce or remove the need for corticosteroid therapy, while maintaining asthma control, said study lead author Professor Klaus Rabe from the Clinic Grosshansdorf in Kiel, Germany.
“Add-on dupilumab therapy significantly reduced oral corticosteroid use while simultaneously reducing severe asthma exacerbations and improving FEV1 in patients with oral corticosteroid-dependent severe asthma,” he said.
“Ultimately, our goal is to find new treatment pathways that allow us to circumvent the use of corticosteroids,” said study co-author Professor Parameswaran Nair from McMaster University, Hamilton, Canada. “Since dupilumab showed a significant improvement on asthma control regardless of eosinophil levels, we may be able to use this treatment for a wider range of patients than we previously thought possible. This might be due to the broad effects on inflammation in asthma of the two proteins [interleukin-4 and interleukin-13] that we were able to block with dupilumab,” he said.
A future in asthma control?
“It is likely that these data will lead to approval of dupilumab for the indication of severe asthma,” said Professors Jeffrey Drazen and David Harrington from the Harvard TH Chan School of Public Health and the Dana-Farber Cancer Institute, respectively, Boston, Massachusetts, US, in an editorial. [N Engl J Med 2018;doi:10.1056/NEJMe1806037]
“This new class of treatments [biologics] is a clear advance in the treatment of severe asthma. But progress falls short of the desired goal. Even though these treatments reduce rates of asthma exacerbations, none of them, even when targeted to groups of patients thought to be most susceptible to this form of treatment [blood eosinophil counts ≥300/mm3], has eliminated exacerbations in all patients and normalized the physiological changes that are the core of asthmatic diathesis,” they said.
Drazen and Harrington called for head-to-head trials to be conducted to assess the comparative effects of the four new biologic treatments for asthma (ie, mepolizumab, reslizumab, benralizumab, and dupilumab) and highlighted the need for further research, particularly pertaining to the identification of other potential markers, that can make treatment more precise in this group of patients.