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2019-08-28

AstraZeneca: Breztri Aerosphere Phase III ETHOS trial met its primary endpoint in chronic obstructive pulmonary disease

At both standard and low budesonide doses, the triple-combination
therapy showed a statistically-significant reduction in the rate of
moderate or severe exacerbations compared with dual-combination
therapies

First time the benefit of two doses of a fixed triple-combination
therapy has been established in a Phase III chronic obstructive
pulmonary disease trial

AstraZeneca today announced positive results from the Phase III ETHOS
trial[ ]for triple-combination therapy Breztri Aerosphere, formerly
PT010, in patients with moderate to very severe chronic obstructive
pulmonary disease (COPD).

At the standard budesonide dose, Breztri Aerosphere
(budesonide/glycopyrronium/formoterol fumarate 320/14.4/9.6mcg)
demonstrated a statistically-significant reduction in the rate of
moderate or severe exacerbations compared with dual-combination
therapies Bevespi Aerosphere (glycopyrronium/formoterol fumarate
14.4/9.6mcg) and PT009 (budesonide/formoterol fumarate 320/9.6mcg).

At half of the budesonide dose, Breztri Aerosphere
(budesonide/glycopyrronium/formoterol fumarate 160/14.4/9.6mcg) also
demonstrated a statistically-significant reduction in the rate of
moderate or severe exacerbations compared with Bevespi Aerosphere and
PT009.

The dual-combination therapies used as comparators in the trial
represent recommended therapeutic classes for the treatment of
COPD.[1]

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said:
"Exacerbations are devastating events for patients and can lead to a
permanent loss of lung function. The Phase III ETHOS trial builds on
the Phase III KRONOS data which together show Breztri Aerosphere's
ability to reduce exacerbation risk in a broad range of patients with
COPD, irrespective of whether they have had an exacerbation in the
previous twelve months. We look forward to sharing these results with
health authorities as soon as possible."

Klaus Rabe, Professor of Pulmonary Medicine at the University of Kiel,
Director of the Department of Pneumology at Clinic Grosshansdorf,
Germany, and Lead Investigator of the ETHOS trial, said: "The Phase
III ETHOS trial results are exciting and demonstrate that Breztri
Aerosphere significantly reduces the rate of exacerbations. This is
also the first time we have seen the benefit of fixed-dose
triple-combination therapy at two inhaled corticosteroid doses, which
could transform treatment practice by allowing physicians to select
the optimal dose for individual patients."

The safety and tolerability of Breztri Aerosphere were consistent with
the known profiles of the dual comparators. In the trial, all
combination therapies were administered in a pressurised metered-dose
inhaler (pMDI) using Aerosphere delivery technology.

The ETHOS trial results will be presented at an upcoming medical
meeting. Breztri Aerosphere has been approved in Japan and is under
regulatory review in China, where it has been granted Priority Review
by the National Medical Products Administration. It is also under
regulatory review in the US and EU.

About ETHOS

ETHOS is a randomised, double-blinded, multi-centre, parallel-group,
52-week trial to assess the efficacy and safety of Breztri Aerosphere
in symptomatic patients with moderate to very severe COPD and a
history of exacerbation(s) in the previous year.[2] Outcomes in the
ETHOS trial included, as a primary endpoint, the rate of moderate or
severe exacerbations. Full trial design details are published in
Respiratory Medicine
(https://www.resmedjournal.com/article/S0954-6111(19)30267-7/fulltext).[3]

Bevespi Aerosphere is a fixed-dose dual bronchodilator in a pMDI,
combining glycopyrronium, a long-acting muscarinic antagonist (LAMA),
and formoterol fumarate, a long-acting beta2-agonist (LABA). PT009 is
a single inhaler, fixed-dose dual-combination therapy of budesonide,
an inhaled corticosteroid (ICS), and formoterol fumarate, a LABA. It
was developed as a relevant comparator in clinical trials for Breztri
Aerosphere.[4,5]

ETHOS involved more than 8,500 patients who had experienced ?1
moderate/severe exacerbation in the previous year and were receiving
at least two inhaled maintenance treatments at entry into the
trial.[2,3 ]

About the ATHENA clinical trial programme

ATHENA is AstraZeneca's Phase III clinical trial programme for Breztri
Aerosphere, which includes more than 15,500 patients globally across
11 trials.[2,3,4,5,6 ]The four key trials are ETHOS, KRONOS, TELOS
and SOPHOS.[2,3,4,5,6]

KRONOS is a Phase III randomised, double-blinded, parallel-group,
24-week, chronic-dosing, multi-centre trial that assessed the
efficacy and safety of Breztri Aerosphere. The trial compared Breztri
Aerosphere with Bevespi Aerosphere, Symbicort Turbuhaler
(budesonide/formoterol fumarate) and PT009. Patients were given two
inhalations twice a day of Breztri Aerosphere, Bevespi Aerosphere,
Symbicort Turbuhaler or PT009. KRONOS involved approximately 1,900
patients with moderate to very severe COPD.[6]

In the KRONOS trial, Breztri Aerosphere met six of seven primary
endpoints versus dual comparators, and PT009 met two non-inferiority
endpoints to support the qualification of PT009 as an active
comparator. As published in The Lancet Respiratory Medicine
(https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(18)30327-8/fulltext),
in a key secondary endpoint, Breztri Aerosphere showed a
statistically-significant 52% reduction in the rate of moderate or
severe COPD exacerbations compared with Bevespi Aerosphere in a
patient population that was not required to have had an exacerbation
in the previous 12 months.[6] Breztri Aerosphere also demonstrated
reductions in the rate of moderate or severe COPD exacerbations
versus PT009 and Symbicort Turbuhaler (18% and 17% respectively),
which were numerically but not statistically-significant
improvements. The incidence of adjudicated pneumonia was low and
comparable in all treatment arms.[6] The primary and secondary
endpoints and treatment comparisons in the KRONOS trial differed
according to regional regulatory requirements.[6]

About Breztri Aerosphere

Breztri Aerosphere has been approved in Japan and is under regulatory
review for approval in China, where it has been granted Priority
Review by the National Medical Products Administration. It is also
under review in the US and EU.

Under the terms of the agreement to acquire Pearl Therapeutics Inc.,
AstraZeneca anticipates making a $150m milestone payment upon US
regulatory approval of Breztri Aerosphere for COPD. This payment
would be the final development and regulatory milestone under that
agreement.

About COPD

COPD is a progressive disease which can cause obstruction of airflow
in the lungs resulting in debilitating bouts of breathlessness.[1] It
affects an estimated 384 million people worldwide and is predicted to
be the third leading cause of death by 2020.[1,7] Improving lung
function, reducing exacerbations and managing daily symptoms such as
breathlessness are important treatment goals in the management of
COPD.[1]

About AstraZeneca in respiratory diseases

Respiratory is one of AstraZeneca's main therapy areas, and our
medicines reached more than 18 million patients as maintenance
therapy in 2018. 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
pressurised metered-dose inhalers and dry powder inhalers, as well as
the Aerosphere delivery technology. The company also has a growing
portfolio of respiratory biologics including Fasenra
(anti-eosinophil, anti-IL-5 receptor alpha), now approved for severe,
eosinophilic asthma and in development for severe nasal polyposis and
other potential indications, and tezepelumab (anti-TSLP), which has
been granted Breakthrough Therapy Designation by the US Food and Drug
Administration in patients with severe asthma and is in Phase III
trials. AstraZeneca's research aims at addressing underlying disease
drivers by focusing on the lung epithelium, lung immunity, lung
regeneration and neuronal functions.

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 therapy areas - Oncology, CVRM and Respiratory. AstraZeneca
operates in over 100 countries and its innovative medicines are used
by millions of patients worldwide. For more information, please visit
astrazeneca.com (http://www.astrazeneca.com/) and follow us on
Twitter @AstraZeneca (https://twitter.com/AstraZeneca).

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References

1. GOLD. Global Strategy for the Diagnosis, Management and Prevention
of COPD, Global Initiative for Chronic Obstructive Lung Disease
(GOLD) 2019. [Online]. Available at: http://goldcopd.org. Last
accessed: August 2019.

2. Clinicaltrials.gov. Study to Assess the Efficacy and Safety of
PT010 Relative to PT003 and PT009 in Subjects With Moderate to Very
Severe COPD (ETHOS). [Online]. Avai...

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