|Topic:||03. Asthma / Adult / Clinical Studies / Allergy, Immunology and Inflammation (AII)|
|Authors:||P. Nair1, S.E. Wenzel2, K.-F. Rabe3, A. Bourdin4, N. Lugogo5, P. Kuna6, P. Barker7, S. Sproule7, S. Ponnarambil8, M. Goldman7; 1Hamilton, ON/CA, 2Pittsburgh, PA/US, 3Großhansdorf/DE, 4Montpellier/FR, 5Durham, NC/US, 6Łódź/PL, 7Gaithersburg, MD/US, 8Cambridge/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).
Conclusions: Benralizumab was well-tolerated and demonstrated significant, clinically relevant OCS-sparing benefits and asthma exacerbation rate reduction compared with placebo.
1Bleecker ER, et al. Lancet. 2016 Sep 5. pii: S0140-6736(16)31324-1. doi: 10.1016/S0140-6736(16)31324-1. [E-pub ahead of print]
2FitzGerald JM, et al. Lancet. 2016 Sep 5. pii: S0140-6736(16)31322-8. doi: 10.1016/S0140-6736(16)31322-8. [E-pub ahead of print]