ATS 2017, WASHINGTON, DC-- An investigational biologic may reduce the need for adults with severe asthma to take an oral corticosteroid to control their asthma, according to a randomized controlled trial presented at the ATS 2017 International Conference. Study findings are being reported simultaneously online, ahead of print in the New England Journal of Medicine.
The biologic is benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, that when delivered subcutaneously, rapidly depletes eosinophils, cells that at high concentrations in the blood and airways lead to frequent asthma exacerbations. Benralizumab was evaluated for patients whose asthma is not well-controlled by high dosages of the standard therapies of inhaled corticosteroids and long-acting β2-agonists and, therefore, were prescribed an add-on oral corticosteroid (prednisone) on a regular basis to boost control.
"Frequent or long-term use of systemic corticosteroids can lead to potentially life-threatening complications, including osteoporosis, diabetes, cardiovascular disease and adrenal suppression," said lead author Parameswaran Nair, MD, PhD, professor of medicine at the Firestone Institute for Respiratory Health, at McMaster University in Hamilton, Canada. "We need new, safe therapies that would replace the need for systemic corticosteroids for patients with severe asthma."
According to the authors, about 5 to 10 percent of people with asthma have a severe form of the disease, and studies have shown that 32 to 45 percent of these people require frequent or maintenance oral corticosteroids.
In this double-blinded, Phase 3 trial, known as ZONDA (named for the dry, warm Andean wind), 220 patients, age 18 to 75, were randomized into three arms: those receiving benralizumab every four weeks, those receiving benralizumab every eight weeks (after three initial four-week doses), and those receiving a placebo.
At the end of 28 weeks, the investigators found:
- The odds of reducing prednisone use was more than four-times greater for patients enrolled in either of the benralizumab arms than placebo.
- Annual exacerbation rates of patients enrolled in either of the benralizumab arms were estimated to be 55 to 70 percent lower than placebo, despite reduction in prednisone use.
- More than one-third of patients enrolled in the benralizumab arms were able to reduce their prednisone dosages by ?90 percent.
- FEV1, the measure of how much air a person can forcefully exhale in one second, was not significantly different between the benralizumab and placebo study arms at the end of the study. However, FEV1 did not decline compared with baseline, despite a significant reduction in the dose of prednisone.
- No major adverse events were related to benralizumab use.
The researchers said that approximately 20 percent of patients did not respond to benralizumab and that future studies would be needed to determine which patients would benefit from the biologic. "It is possible that these patients' asthma was not critically dependent on the eosinophils, or they may not have had significant airway eosinophil activity," Dr. Nair said, adding that "longer term studies of patients with prednisone-dependent asthma are needed before definitive conclusions can be drawn about the long-term efficacy and safety of benralizumab and eosinophil depletion."
Benralizumab is under regulatory review in the United States, European Union, Japan and several other countries.
The study was funded by AstraZeneca.
Contact for media: Parameswaran Nair, MD, PhD, email@example.com
FOR MORE INFORMATION, CONTACT:
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Session: B101 Advances in Asthma
Abstract Presentation Time: Monday, May 22, 2:15 p.m. ET
Location: Walter E. Washington Convention Center Room 206 (South Bldg., Level 2)
Benralizumab Significantly Reduced Oral Corticosteroid Dosages and Asthma Exacerbation Rates for Patients with Severe, Uncontrolled Asthma: Results of the ZONDA Phase III Trial
Authors: P. Nair1, S.E. Wenzel2, K.-F. Rabe3, A. Bourdin4, N. Lugogo5, P. Kuna6, P. Barker7, S. Sproule7, S. Ponnarambil8, M. Goldman7; 1McMaster University & St Joseph's Healthcare - Hamilton, ON/CA, 2University of Pittsburgh - Pittsburgh, PA/US, 3Lungen-Clinic Großhansdorf - Großhansdorf/DE, 4Hôpital Arnaud de Villeneuve- Montpellier/FR, 5Duke University Medical Center - Durham, NC/US, 6Barlicki University Hospital, Medical University of ?ód? - ?ód?/PL, 7AstraZeneca - Gaithersburg, MD/US, 8AstraZeneca - Cambridge/GB; on behalf of the ZONDA study investigators
Rationale: Patients with uncontrolled asthma despite high-dosage inhaled corticosteroids plus long-acting β2-agonists (ICS/LABA) may need add-on oral corticosteroid (OCS) treatment to manage symptoms. However, frequent OCS use is associated with adverse effects. Benralizumab is a humanized, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. In Phase III trials,1,2 benralizumab significantly reduced annual exacerbation rates for patients with severe, eosinophilic asthma. The ZONDA trial (NCT02075255) evaluated OCS dosage-sparing effects of benralizumab for patients with severe asthma receiving high-dosage ICS/LABA and OCS.
Methods: In this RCT, 271 patients (aged 18-75 years) with severe, uncontrolled asthma (eosinophil counts ?150 cells/μL) receiving high-dosage ICS/LABA and OCS (7.5-40 mg/d) entered an initial 2- to 8-week run-in/optimization period during which their OCS dosage was titrated to the minimum effective dosage (baseline) without losing asthma control. Eligible patients were then randomized 1:1:1 to three 28-week treatment groups: benralizumab 30 mg SC either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses every 4 weeks) or placebo SC every 4 weeks. The treatment period comprised a 4-week induction phase (optimized OCS dosage maintained), a 20-week reduction phase (OCS dosage reduced), and a final 4-week maintenance phase (no further OCS dosage adjustment). Primary efficacy endpoint was percentage reduction from baseline in final OCS dosage while maintaining asthma control at Week 28.
Annual asthma exacerbation rate was a secondary endpoint. Each benralizumab regimen was compared with placebo.
Results: Of 220 patients who were randomized and received treatment, 207 (94.1%) completed treatment. Benralizumab significantly reduced final OCS dosages by a median of 75% with the Q4W and Q8W regimens (p<0.001) compared with placebo (25%; table). The odds of a reduction in OCS dosage were 4.09-times greater (Q4W; p<0.001) and 4.12-times greater (Q8W; p<0.001) than with placebo. Benralizumab also significantly reduced annual asthma exacerbation rates by 55% (Q4W; p=0.003) and 70% (Q8W; p<0.001) vs. placebo, despite reduction in OCS dosages in the active treatment groups (table). Adverse events were numerically lower for the benralizumab Q4W and Q8W groups vs. placebo (68.1% and 75.3% vs. 82.7%, respectively).
ZONDA Efficacy Results (full analysis seta)
Percentage reduction from baseline in daily OCS dosage at Week 28
30 mg Q4W
30 mg Q8W
Median (range) baseline OCS dosage, mg/d
Median (range) final OCS dosage at Week 28, mg/db
Median (95% CI) OCS reduction, %
HL estimate (95% CI) for median difference vs. placebo, %c
p-value (Wilcoxon rank sum test)
?90% dosage reductiond
?75% dosage reduction
?50% dosage reduction
>0% dosage reduction
No change or any increase in dosage
Proportional OR (95% CI) (benralizumab/placebo)
p-value (proportional odds modele)
Annual exacerbation rate
Estimated rate (95% CI)
Rate ratio (95% CI)
p-value (negative binomial modelf)
All randomized patients who received any study treatment. bFinal daily oral corticosteroid (OCS) dosage was the dosage at Week 28. If a patient discontinued from the study during a given dosage reduction interval or a patient experienced an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dosage was one dose level greater than that directly preceding the event. cThe Hodges-Lehmann (HL) estimate and 95% confidence intervals (CIs) were the median for the n1 X n2 differences between treatment groups, where n1 was the number of patients in each benralizumab-treated group and n2 was the number of patients receiving placebo. dCumulative percentage reductions. Patients with baseline OCS dosage ?12.5 mg/d were eligible for 100% dosage reductions. eThe proportional odds model was a sensitivity analysis and was not multiplicity protected. Estimate of the proportional odds ratio (OR) for the two treatment groups compared with the placebo group used a proportional odds model, with control for treatment group, region, and baseline OCS dosage. fEstimates via a negative binomial model, with adjustment for treatment group, region, and number of exacerbations in the previous year.
New England Journal of Medicine