FORM 6-K
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
Report
of Foreign Issuer
Pursuant
to Rule 13a-16 or 15d-16 of
the
Securities Exchange Act of 1934
For the
month of September
2021
Commission
File Number: 001-11960
AstraZeneca PLC
1
Francis Crick Avenue
Cambridge
Biomedical Campus
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United
Kingdom
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Fixed-dose combination of albuterol and budesonide (PT027)
demonstrated significant benefits for asthma patients in MANDALA
and DENALI Phase III trials
9 September 2021 07:00 BST
Fixed-dose combination of albuterol and budesonide (PT027)
demonstrated significant benefits for asthma patients in MANDALA
and DENALI Phase III trials
PT027 significantly reduced the risk of severe exacerbations
compared to albuterol in patients with moderate to severe asthma in
MANDALA trial when used as a rescue medicine in response to
symptoms
PT027 significantly improved lung function compared to individual
components in mild to moderate asthma in DENALI trial
Positive high-level results from the MANDALA and DENALI Phase III
trials of PT027 (albuterol/budesonide), at both 180/160mcg and
180/80mcg doses, met all primary endpoints demonstrating
statistically significant benefits in patients with asthma
versus individual components albuterol, also known as
salbutamol (180mcg) and budesonide (160mcg).
PT027 is a potential first-in-class inhaled, fixed-dose
combination of albuterol, a short-acting beta2-agonist (SABA), and
budesonide, an inhaled corticosteroid (ICS), being developed by
AstraZeneca and Avillion.
The MANDALA trial met the primary endpoint, with PT027
demonstrating statistically significant and clinically meaningful
reductions in the risk of severe exacerbations compared to
albuterol, when used as a rescue medicine in response to
symptoms. The trial included 3,132 patients with moderate to severe
asthma taking maintenance ICS with or without additional controller
medicines.
The DENALI trial met the dual primary endpoints, with PT027 showing
a statistically significant improvement in lung function measured
by forced expiratory volume in one second (FEV1), compared to the
individual components albuterol and budesonide, and compared to
placebo. The trial included 1,001 patients with mild to moderate
asthma previously treated either with a SABA as needed alone or in
addition to low-dose maintenance ICS therapy.
Asthma is a chronic, inflammatory, fluctuating respiratory
disease1 that
affects as many as 339 million adults and children
worldwide,1 including
over 25 million in the US.2 Inflammation
is a distinctive feature of asthma3 and
plays a key role in asthma symptoms,4 exacerbations5 and
deaths.5
Bradley E. Chipps, Past President of the American College of
Allergy, Asthma & Immunology and Medical Director of Capital
Allergy & Respiratory Disease Center in Sacramento, US, said:
"Severe asthma exacerbations are a significant burden for
many asthma patients of all ages resulting in impaired quality
of life, hospitalisation, treatment with systemic corticosteroids
which can lead to serious side effects, and the possibility of
premature death. Many millions of patients globally rely on their
rescue inhaler to alleviate acute symptoms, but this does not treat
the underlying inflammation in asthma. The MANDALA and DENALI
trials demonstrate an albuterol/budesonide rescue inhaler can
address inflammation and prevent exacerbations, making PT027 an
important potential new treatment option for
patients."
Mene Pangalos, Executive Vice President, BioPharmaceuticals
R&D, said: "All patients with asthma are at risk of severe
exacerbations, regardless of their disease severity and many are
known to overuse short-acting bronchodilators. These exciting
results with PT027 bring us one step closer to providing
an innovative and superior treatment approach for asthma
by preventing exacerbations."
The safety and tolerability of PT027 in both trials were consistent
with the known profiles of the components. Detailed data from
MANDALA and DENALI will be presented at an upcoming medical
meeting.
Asthma
Patients with asthma experience recurrent breathlessness and
wheezing, which varies over time, and in severity and
frequency.4 These
patients are at risk of severe exacerbations regardless of their
disease severity, adherence to treatment or level of
control.6-7
There are an estimated 176 million asthma exacerbations globally
per year,8 including
more than 10 million in the US;2 these
are physically threatening and emotionally significant for many
patients9 and
can be fatal.1,4
Inflammation is central to both asthma symptoms4 and
exacerbations.5 Many
patients experiencing asthma symptoms use a SABA as a rescue
medicine, however, taking a SABA alone does not address
inflammation, leaving patients at risk of severe
exacerbations,10 which
can result in impaired quality of life,11 hospitalisation12 and
frequent oral corticosteroid (OCS) use.12 Repeated
courses of OCS therapy are associated with an increased risk of
systemic side effects including pneumonia, osteoporosis and type 2
diabetes.13,14 International
recommendations from the Global Initiative for Asthma no longer
recommend SABA as the preferred rescue therapy.4
MANDALA
MANDALA15,16 is
a Phase III, randomised, double-blind, multicentre, parallel-group,
event-driven trial evaluating the efficacy and safety of PT027
compared to albuterol on the time to first severe asthma
exacerbation in 3,132 adults and children aged four years and
older with moderate to severe asthma taking ICS alone or in
combination with a range of asthma maintenance therapies, including
long-acting beta2-agonists (LABA), leukotriene receptor antagonists
(LTRA), long-acting muscarinic antagonists (LAMA) or theophylline.
The trial comprised a two to four-week screening period, at least a
24-week treatment period and a two-week post-treatment follow-up
period.
Patients were randomly assigned to one of the following three
treatment groups in a 1:1:1 ratio: PT027 180/160mcg
(excluding patients aged 11 years or younger), PT027
180/80mcg or albuterol 180mcg, taken as a rescue medicine
in response to symptoms. PT027 and the albuterol comparator were
delivered in a pressurised metered-dose inhaler (pMDI) using
AstraZeneca's Aerosphere delivery technology. The primary efficacy
endpoint was the time to first severe asthma exacerbation during
the treatment period. Secondary endpoints included severe
exacerbation rate (annualised), total systemic corticosteroid
exposure over the treatment period, asthma control and
health-related quality of life.
DENALI
DENALI17,18 is
a Phase III, randomised, double-blind, placebo-controlled,
multicentre, parallel-group trial evaluating the efficacy and
safety of PT027 compared to its components albuterol and budesonide
on improvement in lung function in 1,001 adults and children aged
four years and older with mild to
moderate asthma previously treated either with SABA as
needed alone or in addition to regular low-dose ICS maintenance
therapy. The trial comprised a two-to-four-week screening period, a
12-week treatment period and a two-week post-treatment follow-up
period.
Patients were randomly assigned to one of the following five
treatment groups in a 1:1:1:1:1 ratio: PT027 180/160mcg four times
daily (excluding patients aged 11 years or younger), PT027
180/80mcg four times daily, albuterol 180mcg four times daily,
budesonide 160mcg four times daily and placebo four times
daily (excluding patients aged 11 years or
younger). PT027 and the albuterol and budesonide comparators
were delivered in a pMDI using
AstraZeneca's Aerosphere delivery technology. The dual primary
efficacy endpoints were a change from baseline in FEV1 area under
the curve 0-6 hours over
12 weeks of PT027 compared to budesonide to assess the effect of
albuterol and a change from baseline in trough FEV1 at
week 12 of PT027 compared to albuterol to assess the effect
of budesonide. Secondary endpoints included the time to onset and
duration of response on day one, number of patients who achieved a
clinically meaningful improvement in asthma control from baseline
at week 12 and trough FEV1 at week one.
PT027
PT027 is a potential first-in-class SABA/ICS rescue treatment
for asthma in the US, to be taken as needed in response to
symptoms. It is an inhaled, fixed-dose combination of albuterol
(also known as salbutamol), a SABA, and budesonide, a
corticosteroid, and is being developed in a pMDI using
AstraZeneca's Aerosphere delivery
technology.
AstraZeneca and Avillion collaboration
In March 2018, AstraZeneca and Avillion signed an agreement to
advance PT027 through a global clinical development programme for
the treatment of asthma. Under the terms of the agreement, Avillion
became the trial sponsor responsible for executing and funding the
multicentre, global clinical trial programme for PT027 through to
regulatory decision in the US. Following the successful approval of
PT027, AstraZeneca has the option, upon certain financial payments,
to commercialise the medicine in the US.
AstraZeneca in Respiratory & Immunology
Respiratory & Immunology, part of BioPharmaceuticals, is one of
AstraZeneca's main disease areas and is a key growth driver for the
Company.
AstraZeneca is an established leader in respiratory care with a
50-year heritage. The Company aims to transform the treatment of
asthma and COPD by focusing on earlier biology-led treatment,
eliminating preventable asthma attacks, and removing COPD as a
top-three leading cause of death. The Company's early respiratory
research is focused on emerging science involving immune
mechanisms, lung damage and abnormal cell-repair processes in
disease and neuronal dysfunction.
With common pathways and underlying disease drivers across
respiratory and immunology, AstraZeneca is following the science
from chronic lung diseases to immunology-driven disease areas. The
Company's growing presence in immunology is focused on five mid- to
late-stage franchises with multi-disease potential, in areas
including rheumatology (including systemic lupus erythematosus),
dermatology, gastroenterology, and systemic eosinophilic-driven
diseases. AstraZeneca's ambition in Respiratory & Immunology is
to achieve disease modification and durable remission for millions
of patients worldwide.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led
biopharmaceutical company that focuses on the discovery,
development, and commercialisation of prescription medicines in
Oncology, Rare Diseases, and BioPharmaceuticals, including
Cardiovascular, Renal & Metabolism, and Respiratory &
Immunology. Based in Cambridge, UK, AstraZeneca operates in over
100 countries and its innovative medicines are used by millions of
patients worldwide. Please visit astrazeneca.com and
follow the Company on Twitter @AstraZeneca.
Contacts
For details on how to contact the Investor Relations Team, please
click here.
For Media contacts, click here.
References
1. The Global Asthma
Network. The Global Asthma Report 2018. [Online]. Available
at: http://www.globalasthmareport.org/Global%20Asthma%20Report%202018.pdf.
[Last accessed: 2 July 2021].
2. CDC. Most
Recent National Asthma Data. [Online]/ Available at:
https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm. [Last
accessed: 2 July 2021].
3. Wenzel SE. Asthma phenotypes: the
evolution from clinical to molecular
approaches. Nat Med. 2012;18:716-725.
4. Global
Initiative for Asthma. 2021 GINA Report, Global Strategy
for Asthma Management and Prevention. [Online]. Available
at: https://ginasthma.org/wp-content/uploads/2021/04/GINA-2021-Main-Report_FINAL_21_04_28-WMS.pdf [Last
accessed: July 2021]
5. Wark PA, et al. Asthma exacerbations· 3:
pathogenesis. Thorax. 2006 Oct
1;61(10):909-15.
6. Price D, et al. Asthma control and management in 8,000 European
patients: the REcognise Asthma and LInk to Symptoms and Experience
(REALISE) survey. NPJ Prim Care Respir
Med. 2014;24:14009.
7. Papi
Am, et
al.
Relationship of inhaled corticosteroid adherence to asthma
exacerbations in patients with moderate-to-severe
asthma. J
Allergy Clin Immunol Pract. 2018;6(6):1989-98.e3.
8.
AstraZeneca Pharmaceuticals. Data on File. Budesonide/formoterol
Data on File: Annual Rate of Asthma Exacerbations Globally. (ID:
SD-3010-ALL-0017).
9. Sastre
J, et
al. Insights, attitudes,
and perceptions about asthma and its treatment: a multinational
survey of patients from Europe and Canada. World Allergy Organ
J. 2016;9:13.
10. Nwaru BI, et al. Overuse of short-acting
b2-agonists in asthma is associated with increased risk of
exacerbation and mortality: a nationwide cohort study of the global
SABINA programme. Eur Respir
J.
2020;55(4):1901872.
11. Lloyd A, et al. The impact of asthma
exacerbations on health-related quality of life in moderate to
severe asthma patients in the UK. Prim Care Respir
J.
2007;16(1):22-7.
12. Bourdin A, et al. ERS/EAACI statement on
severe exacerbations in asthma in adults: facts, priorities and key
research questions. Eur Respir
J.
2019;54(3):1900900.
13. Price DB, et al. Adverse outcomes from initiation of systemic
corticosteroids for asthma: long-term observational
study. J Asthma
Allergy. 2018;11:193-204.
14. Sullivan PW, et al.
Oral corticosteroid exposure and adverse effects in asthmatic
patients. J
Allergy Clin Immunol. 2018;141:110-116.e7
15. Clinicaltrials.gov. A
Study to Assess the Efficacy and Safety of Budesonide/Albuterol
Metered-dose Inhaler (BDA MDI/PT027) in Adults and Children 4 Years
of Age or Older With Asthma (MANDALA). Available
at https://clinicaltrials.gov/ct2/show/NCT03769090.
[Last accessed: 2 July 2021].
16. Chipps BE, et al. Evaluation of the
Efficacy and Safety of As-Needed PT027 Budesonide/Albuterol MDI)
Compared to As-Needed Albuterol MDI in Adults and Children 4 Years
of Age or Older with Uncontrolled Moderate to Severe Asthma: Design
of the Mandala Study. Am. J. Respir. Crit. Care
Med.
2020;201:A3015.
17. Clinicaltrials.gov. A
Study to Assess the Efficacy and Safety of Budesonide/Albuterol
Metered-dose Inhaler (BDA MDI/PT027) Used 4 Times Daily in Adults
and Children 4 Years of Age or Older With Asthma (DENALI).
Available at https://clinicaltrials.gov/ct2/show/NCT03847896.
[Last accessed: 2 July 2021].
18. AstraZeneca
Pharmaceuticals. Data on File. DENALI clinical trial protocol
Data on File (ID: 121792).
Adrian Kemp
Company Secretary
AstraZeneca PLC
SIGNATURES
Pursuant
to the requirements of the Securities Exchange Act of 1934, the
Registrant has duly caused this report to be signed on its behalf
by the undersigned, thereunto duly authorized.
Date:
09 September2021
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By: /s/
Adrian Kemp
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Name:
Adrian Kemp
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Title:
Company Secretary
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