Phase III ZONDA trial for benralizumab shows ability to reduce oral steroid use in severe asthma patients

Patients treated with benralizumab were more than four times as likely to reduce oral corticosteroid (OCS) dose than those on placebo

Benralizumab also reduced overall exacerbation rates by 70% and exacerbations requiring emergency room visits or hospitalisations by 93% in patients with severe, uncontrolled eosinophilic asthma

Trial results published simultaneously in New England Journal of Medicine

22 May 2017

Results from the Phase III ZONDA trial presented at the 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 today online 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% for patients treated with benralizumab versus 25% with placebo.

The ZONDA trial demonstrated significant outcomes for secondary endpoints. For OCS reduction in the 8-week dosing regimen:

• 66% of benralizumab-treated patients reduced OCS doses by ≥50% compared with 37% receiving placebo
• 37% of benralizumab-treated patients reduced OCS doses by ≥90% compared with 12% receiving placebo
• 52% of benralizumab-treated patients who were eligible to discontinue OCS per the trial protocol were able to stop OCS use completely, compared with 19% receiving placebo

Analysis of prevention or reduction of acute asthma events in benralizumab treated patients on the 8-week dosing regimen demonstrated:

• 70% reduction in overall annual exacerbation rate compared with placebo
• 93% reduction in exacerbations requiring emergency room visits or hospitalisations compared with placebo

Dr. Parameswaran Nair, Professor of Respiratory Medicine at McMaster University in Hamilton, Canada and the lead investigator of the trial, said: “Benralizumab showed an impressive clinical efficacy by reducing exacerbations rate by up to 70% at the same time enabling patients with severe asthma to significantly lower their prednisone dose and maintain their lung function. This is likely due to its unique mechanism of action of inhibiting the receptor for interleukin-5 and potentially depleting blood and airway eosinophils."

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer, said: “One of the known clinical characteristics of the eosinophilic asthma phenotype is an over reliance on oral steroids to manage severe uncontrolled disease. 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 hospitalisations 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 4-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%) 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 is not approved anywhere in the world, but is under regulatory review in the US, EU, Japan and several other countries with a US PDUFA date during the fourth quarter of 2017.

NOTES TO EDITORS

About Severe Asthma

Asthma affects 315 million individuals worldwide, and up to 10% of asthma patients have severe asthma which may be uncontrolled despite high doses of standard-of-care asthma controller medicines and can require the use of chronic oral corticosteroids (OCS).

Severe uncontrolled asthma is debilitating and potentially fatal with patients experiencing frequent exacerbations and significant limitations on lung function and quality of life. Severe, uncontrolled asthma has an eight times higher risk of mortality than severe asthma.

Uncontrolled asthma can lead to a dependence on OCS, with systemic steroid exposure potentially leading to serious and irreversible short- and long-term adverse effects, including weight gain, diabetes, osteoporosis, glaucoma, anxiety, depression, cardiovascular disease and immunosuppression. There is also a significant physical and socio-economic burden of severe asthma with these patients accounting for 50% of asthma-related costs.

About the ZONDA Trial

ZONDA was a 28-week, randomised, double-blind, parallel-group, placebo-controlled, multicentre Phase III trial which included 220 adult patients with severe uncontrolled asthma requiring treatment with high-dosage ICS plus a LABA and chronic OCSs and blood eosinophil counts of at least 150 cells/μL^[i]  The trial assessed the effects of benralizumab (30 mg every 4 weeks or every 8 weeks; first three doses every 4 weeks) versus placebo on OCS dose reduction while maintaining asthma control for adult patients with severe asthma. The primary endpoint was the percentage change in OCS dose from baseline to week 28.

Patients underwent randomisation at week 0 to receive benralizumab or placebo, and entered the 4-week induction phase, during which optimised OCS doses were maintained. In the subsequent reduction phase (weeks 4–24), OCS doses were reduced by 2.5–5.0 mg/d at 4-weekly intervals. Only patients with optimised baseline OCS doses ≤12.5 mg/d were eligible for 100% dose reduction. See the New England Journal of Medicine manuscript published online today for additional information on OCS dose protocol in the trial.

About Benralizumab

Benralizumab is an anti-eosinophil monoclonal antibody that induces direct, and near-complete depletion of eosinophils via antibody dependent cell-mediated cytotoxicity (ADCC). Depletion of circulating eosinophils is rapid, with an onset of action within 24 hours as confirmed in early phase I/II trials. In the pivotal Phase III trials, SIROCCO and CALIMA benralizumab demonstrated significant reduction in exacerbations and improved lung function and asthma symptoms in severe uncontrolled eosinophilic asthma patients. Eosinophils are the biological effector cells that drive inflammation and airway hyper-responsiveness in approximately 50% of asthma patients, leading to frequent exacerbations, impaired lung function and asthma symptoms. Benralizumab is not approved anywhere in the world, but is under regulatory review in the US, EU, Japan and several other countries.

Benralizumab was developed by MedImmune, AstraZeneca’s global biologics research and development arm and is in-licensed from BioWa, Inc., a wholly-owned subsidiary of Kyowa Hakko Kirin Co., Ltd.

About AstraZeneca in Respiratory Disease

Respiratory disease is one of AstraZeneca’s main therapy areas, and the Company has a growing portfolio of medicines that reached more than 18 million patients in 2016. AstraZeneca’s aim is to transform asthma and COPD treatment through inhaled combinations at the core of care, biologics for the unmet needs of specific patient populations, and scientific advancements in disease modification.

The Company is building on a 40-year heritage in respiratory disease and AstraZeneca’s capability in inhalation technology spans both pMDIs and dry powder inhalers, as well as the innovative Co-Suspension^TM Delivery Technology. The company’s biologics include benralizumab (anti-eosinophil, anti-IL-5rɑ), which has been accepted for regulatory review in the US, EU and Japan, tralokinumab (anti-IL-13), which is currently in Phase III, and tezepelumab (anti-TSLP), which successfully achieved its Phase IIb primary endpoint. AstraZeneca’s research is focused on addressing underlying disease drivers focusing on the lung epithelium, lung immunity and lung regeneration.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three main therapy areas - Oncology, Cardiovascular & Metabolic Diseases and Respiratory. The Company also is selectively active in the areas of Autoimmunity, Neuroscience and Infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca.com and follow us on Twitter @AstraZeneca.

CONTACTS

[i] In-House Data, AstraZeneca Pharmaceuticals LP.  Clinical Study Report D3250C00020.