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2018-09-16

AstraZeneca: The Lancet Respiratory Medicine publishes first Phase III trial for PT010 triple combination therapy in modera...

Data from the KRONOS trial presented at the European Respiratory
Society (ERS) International Congress 2018

AstraZeneca today announced publication of results from the KRONOS
Phase III trial which evaluated the efficacy and safety of triple
combination therapy PT010 (budesonide/ glycopyrronium/formoterol
fumarate) versus dual combination therapies Bevespi Aerosphere
(glycopyrronium/formoterol fumarate), Symbicort Turbuhaler
(budesonide/formoterol fumarate) and PT009 (budesonide/formoterol
fumarate) in patients with moderate to very severe chronic
obstructive pulmonary disease (COPD) regardless of whether or not
they had an exacerbation in the prior year.1

The KRONOS trial met eight of the nine primary lung function endpoints
and, in a key secondary endpoint, PT010 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. PT010 also demonstrated reductions in the rate of
moderate or severe COPD exacerbations versus PT009 and Symbicort (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.1 Further details on the
primary endpoints are outlined below.

The data were presented today at the European Respiratory Society
(ERS) International Congress 2018 in Paris, France, and published in
The Lancet Respiratory Medicine
(https://clicktime.symantec.com/a/1/jqLVcgwdQNWM3VwmTKbMYigxQYXTqRXgZ44Vi...).1

Dr Colin Reisner, Head of Respiratory, Global Medicines, said: "We are
encouraged by the results of the KRONOS trial which demonstrate
PT010's efficacy in improving lung function and its potential value
as a triple combination therapy for patients with COPD. Importantly,
PT010 also halved the rate of moderate or severe exacerbations
compared to glycopyrronium/formoterol fumarate and we look forward to
the ETHOS exacerbation trial results in 2019 to further characterise
PT010."

Gary Ferguson, Professor of the Pulmonary Research Institute of
Southeast Michigan, Livonia, Michigan and lead author of the KRONOS
trial publication, said: "Preventing exacerbations is a priority in
the management of COPD because they are known to have an impact on
lung function and mortality, and patients are at risk even if they
haven't had an exacerbation in the previous 12 months. The KRONOS
trial demonstrated that PT010 reduces the risk of an exacerbation
versus LAMA/LABA combination therapy in symptomatic COPD patients
regardless of whether or not they've had an exacerbation in the
previous year."

There were no new or unexpected safety or tolerability signals for
PT010 in the KRONOS trial, and the adverse events profile was
consistent with that observed in previous trials. The most frequently
reported adverse events were nasopharyngitis, upper respiratory tract
infection, COPD, bronchitis, muscle spasms, dysphonia, hypertension,
dyspnoea, back pain and nausea. The incidence of adjudicated
pneumonia was low and comparable among PT010 (1.9%), Bevespi
Aerosphere (1.6%), PT009 (1.9%) and Symbicort Turbuhaler (1.3%).

AstraZeneca anticipates making the first regulatory submissions for
PT010 in the second half of 2018.

- ENDS -

NOTES TO EDITORS

About COPD

Chronic obstructive pulmonary disease (COPD) is a progressive disease
which can cause obstruction of airflow in the lungs resulting in
debilitating bouts of breathlessness.2 It affects an estimated 384
million people worldwide3 and is predicted to be the third leading
cause of death by 2020.2 Improving lung function, reducing
exacerbations and managing daily symptoms such as breathlessness are
important to the management of COPD.2

COPD exacerbations significantly impair quality of life and are linked
to disease progression, accelerated decline in lung function,
increased hospitalisations and mortality.4 Even one severe
exacerbation carries an increased risk of mortality.5

About PT010 and the Aerosphere portfolio

PT010 is a single inhaler, fixed-dose triple combination therapy of
budesonide, an inhaled corticosteroid (ICS) with glycopyrronium, a
long-acting muscarinic agonist (LAMA), and formoterol fumarate, a
long-acting beta2-agonist (LABA). It is being developed using
AstraZeneca's Aerosphere Delivery Technology. Aerosphere Delivery
Technology is also the platform for the approved medicine Bevespi
Aerosphere.

About KRONOS and the ATHENA clinical trial programme

KRONOS is a randomised, double-blind, parallel-group, 24-week,
chronic-dosing, multi-centre trial to assess the efficacy and safety
of PT010. The trial compared PT010 to Bevespi Aerosphere
(glycopyrronium/formoterol fumarate 14.4/9.6µg pMDI), Symbicort
Turbuhaler (budesonide/formoterol fumarate 400/12µg) and PT009
(budesonide/formoterol fumarate 320/9.6µg using Aerosphere Delivery
Technology in a pressurised metered-dose inhaler (pMDI). Patients
were given two inhalations twice a day of PT010, Bevespi Aerosphere,
Symbicort Turbuhaler or PT009. KRONOS involved approximately 1,900
patients with moderate to very severe COPD. Around three-quarters of
patients (74%) had not reported an exacerbation in the previous 12
months.

In the KRONOS trial, eight of the nine primary comparisons were met,
including two non-inferiority endpoints to support PT009 as a
comparator. The Lancet Respiratory Medicine publication reports on
six of the primary comparisons in the trial. The primary and
secondary endpoints and treatment comparisons in the KRONOS trial
differed according to regional regulatory requirements.1

ATHENA is AstraZeneca's Phase III clinical trial programme for PT010,
which includes more than 15,500 patients globally across 11
trials.6,7,8,9 The four key trials are ETHOS, KRONOS, TELOS and
SOPHOS. ETHOS, TELOS and SOPHOS include low and high doses of ICS and
stratification of patients by eosinophil levels as part of
randomisation, for PT010 and PT009 respectively.7,8,9

+---------------------+-------------------+---------------------------+
|KRONOS Primary endpoints |
+---------------------+-------------------+---------------------------+
|Endpoint |Timepoint |Comparison/Results |
+---------------------+-------------------+---------------------------+
| | |PT010 vs PT009 |
+---------------------+-------------------+---------------------------+
|Post-dose FEV1 AUC0-4|Over 24 weeks |Met (p<0.0001) |
+---------------------+-------------------+---------------------------+
|At Week 24 |Met (p<0.0001) |
+---------------------+-------------------+---------------------------+
| |PT010 vs Symbicort |
+---------------------+-------------------+---------------------------+
|Over 24 weeks |Met (p<0.0001) |
+---------------------+-------------------+---------------------------+
| | |PT010 vs Bevespi Aerosphere|
+---------------------+-------------------+---------------------------+
|Pre-dose trough FEV1 |Over 24 weeks |Met (p=0.0139) |
+---------------------+-------------------+---------------------------+
|At Week 24 |Not met (p=0.2375) |
+---------------------+-------------------+---------------------------+
| |PT009 vs Symbicort |
+---------------------+-------------------+---------------------------+
|Over 24 weeks |Met -- non-inferior|
+---------------------+-------------------+---------------------------+

About Symbicort

Symbicort is a combination formulation containing budesonide, an ICS,
and formoterol, a LABA, in a single inhaler. Symbicort is approved in
approximately 120 countries to treat COPD either as Symbicort
Turbuhaler or Symbicort pMDI. Indications differ by country/region
and the respective prescribing information or Summary of Product
Characteristics (SmPC) should be consulted.

About Bevespi Aerosphere

Bevespi Aerosphere is a fixed-dose dual bronchodilator combining
glycopyrronium, a long-acting muscarinic agonist (LAMA), and
formoterol fumarate, a long-acting beta2-agonist (LABA). Bevespi
Aerosphere is the first and only LAMA/LABA with Aerosphere Delivery
Technology. Results from an imaging trial have shown that Bevespi
Aerosphere effectively delivers medicine to both the large and small
airways. Aerosphere Delivery Technology is also the platform for
potential new medicines including PT010.

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 2017. 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-5r?), now approved for severe eosinophilic
asthma and in development for severe nasal polyposis, and tezepelumab
(anti-TSLP), which is in Phase III trials and achieved its Phase IIb
primary and secondary endpoints. 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 therapy areas - Oncology, Cardiovascular, Renal & Metabolism
and Respiratory. 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 Twi...

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