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2017-05-22

AstraZeneca: 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

Results from the Phase III ZONDA trial
(https://cms.psav.com/cPaper2014/viewing/view.php?access_hash=c6af0bc86a2...)
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.

- ENDS -

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/?L[i]
(http://file:///C:/Users/kdzn235/AppData/Local/Microsoft/Windows/Temporar...)
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-SuspensionTMDelivery Technology. The company's biologics include
benralizumab (anti-eosinophil, anti-IL-5r?), 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.

Media Enquiries
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