Results from the Phase III Zonda trial presented at the recent American Thoracic Society (ATS) 2017 International Congress demonstrated that adding benralizumab to standard of care allowed patients dependent on OCS to significantly reduce or discontinue steroids while maintaining asthma control.
Detailed results of the Zonda study were published yesterday in the New England Journal of Medicine.
The trial achieved its primary efficacy endpoint, demonstrating statistically significant and clinically relevant reduction in daily maintenance OCS use with two benralizumab dosing regimens compared with placebo.
Patients treated with benralizumab were more than four times as likely to reduce their OCS dose than those in the placebo group. The median reduction in OCS dose was 75 per cent for patients treated with benralizumab versus 25 per cent with placebo.
Zonda was a 28-week, randomized, double-blind, parallel-group, placebo-controlled, multicentre Phase III trial which included 220 adult patients with severe uncontrolled asthma requiring treatment with high-dose ICS plus a LABA and chronic OCSs and blood eosinophil counts of at least 150 cells/μL.
Benralizumab is an anti-eosinophil monoclonal antibody that induces direct and near-complete depletion of eosinophils via antibody dependent cell-mediated cytotoxicity (ADCC).
Respiratory disease is one of AstraZeneca’s main therapy areas.
The ZONDA trial demonstrated significant outcomes for secondary endpoints. For OCS reduction in the 8-week dosing regimen:
- 66 per cent of benralizumab-treated patients reduced OCS doses by ≥50 per cent compared with 37 per cent receiving placebo
- 37 per cent of benralizumab-treated patients reduced OCS doses by ≥90 per cent compared with 12 per cent receiving placebo
- 52 per cent of benralizumab-treated patients who were eligible to discontinue OCS per the trial protocol were able to stop OCS use completely, compared to 19 per cent receiving placebo
- Analysis of prevention or reduction of acute asthma events in benralizumab-treated patients on the 8-week dosing regimen demonstrated:
- 70 per cent reduction in overall annual exacerbation rate compared with placebo
- 93 per cent reduction in exacerbations requiring emergency room visits or hospitalizations compared with placebo
“Benralizumab showed an impressive clinical efficacy by reducing exacerbations rate by up to 70 per cent at the same time enabling patients with severe asthma to significantly lower their prednisone dose and maintain their lung function,” said Dr. Parameswaran Nair, Professor of Respirology Medicine at McMaster University in Hamilton, Ontario, Canada and the lead investigator of the trial. “This is likely due to its unique mechanism of action of inhibiting the receptor for interleukin-5 and potentially depleting blood and airway eosinophils.”
“One of the known clinical characteristics of the eosinophilic asthma phenotype is an over-reliance on oral steroids to manage severe uncontrolled disease.,” said Sean Bohen, executive vice president, global medicines development and chief medical officer. “What is exciting about the Zonda trial is that we have shown benralizumab delivers a clinically meaningful OCS reduction alongside a substantial reduction in asthma exacerbation rate including emergency treatment or hospitalizations in this difficult-to-treat patient population.”
The Zonda trial evaluated the effect of benralizumab 30 mg administered subcutaneously (SC) using either an 8- or four-week dosing regimen for 28 weeks in adult patients with severe, uncontrolled eosinophilic asthma receiving high-dose inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) and OCS with or without additional asthma controllers.
Benralizumab was well-tolerated, with an overall adverse event profile like that of placebo and that observed in previous Phase III trials. The most common adverse events (≥10 per cent) in benralizumab-treated patients observed in ZONDA were nasopharyngitis, worsening asthma and bronchitis.
The data from the Zonda trial, along with the pivotal Phase III SIROCCO and CALIMA trials, were included in regulatory submissions for benralizumab. Benralizumab has not been approved anywhere in the world but is under regulatory review in the US, EU, Canada, Japan and several other countries with a US PDUFA date during the fourth quarter of 2017.