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 January 2023
Commission File
Number: 001-11960
AstraZeneca
PLC
1
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Cambridge
Biomedical Campus
Cambridge CB2
0AA
United
Kingdom
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AstraZeneca
PLC
INDEX
TO EXHIBITS
1.
Airsupra (PT027) approved in US for asthma
11
January 2023 13:00 GMT
Airsupra (PT027)
approved in the US for asthma
First and only rescue medication approved in the US for as-needed
use to reduce risk of asthma exacerbations
Airsupra (albuterol/budesonide), formerly known as
PT027, has been approved in the US for the as-needed treatment or
prevention of bronchoconstriction and to reduce the risk of
exacerbations in people with asthma aged 18 years and
older.
The approval by the Food and Drug Administration
(FDA) was based on results from the MANDALA and DENALI Phase III
trials.1,2 In
MANDALA, Airsupra significantly reduced the risk of severe
exacerbations compared to albuterol in patients with moderate to
severe asthma when used as an as-needed rescue medication in
response to symptoms.1 Importantly,
in the secondary endpoint of mean annualised total systemic
corticosteroid exposure, Airsupra demonstrated a significant reduction
compared to albuterol at the approved dose of 180mcg
albuterol/160mcg budesonide.1 In
DENALI, Airsupra significantly improved lung function
compared to the individual components albuterol and budesonide in
patients with mild to moderate asthma.2
Airsupra is a first-in-class, pressurised
metered-dose inhaler (pMDI), fixed-dose combination rescue
medication containing albuterol, a short-acting beta2-agonist
(SABA), and budesonide, an anti-inflammatory inhaled corticosteroid
(ICS) in the US. It is being developed by AstraZeneca and
Avillion.
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: "People with asthma are at risk of severe exacerbations
regardless of their disease severity or level of control. Current
albuterol rescue inhalers alleviate acute symptoms, but do not
treat the underlying inflammation in asthma. The approval
of Airsupra means that for the first time, adults with
asthma in the US have a rescue treatment to manage both their
symptoms and the inflammatory nature of their
disease."
Mene Pangalos, Executive Vice President,
BioPharmaceuticals R&D, AstraZeneca, said: "With patients
experiencing more than 10 million asthma exacerbations each year in
the US and uncontrolled asthma expected to cost the US economy
billions of dollars in direct medical costs alone over the next 20
years, today's positive decision is good news for those adults with
asthma who make up more than 80% of asthma patients in the US.
Physicians will be able to offer their
patients Airsupra, an important new rescue treatment that reduces
the risk of asthma exacerbations."
Asthma is a chronic, inflammatory respiratory
disease with variable symptoms that affects as many as 262 million
people worldwide.3 In
the US over 21 million adults have asthma, representing more than
80% of the total number of people with asthma.4 Adults
have 8.5 million exacerbations each year in the
US.4 Uncontrolled
asthma will cost the US economy an estimated $300 billion (in 2018
dollar values) in the next 20 years in direct medical costs
alone.5
The safety and tolerability
of Airsupra in both trials were consistent with the
known profiles of the components,1,2 with
the most common adverse events including headache, oral
candidiasis, cough and dysphonia.6
Results from the MANDALA trial were published in
the New
England Journal of Medicine in May 2022.1
Notes
Asthma
Asthma is a chronic, inflammatory respiratory
disease with variable symptoms that affects as many as 262 million
people worldwide,3 including
over 25 million in the US.4
Patients with asthma experience recurrent
breathlessness and wheezing, which varies over time, and in
severity and frequency.7 These
patients are at risk of severe exacerbations regardless of their
disease severity, adherence to treatment or level of
control.8,9
There are an estimated 136 million asthma
exacerbations globally per year,10 including
more than 10 million in the US;4 these
are physically threatening and emotionally significant for many
patients11 and
can be fatal.3,12
Inflammation is central to both asthma
symptoms8 and
exacerbations.13 Many
patients experiencing asthma symptoms use a SABA (e.g. albuterol)
as a rescue medicine;14-16 however,
taking a SABA alone does not address inflammation, leaving patients
at risk of severe exacerbations,17 which
can result in impaired quality of life,18 hospitalisation19 and
frequent oral corticosteroid (OCS) use.19 Treatment
of exacerbations with as few as 1-3 short courses of OCS are
associated with an increased risk of adverse health conditions
including type 2 diabetes, depression/anxiety, renal impairment,
cataracts, cardiovascular disease, pneumonia and
fracture.20 International
recommendations from the Global Initiative for Asthma no longer
recommend SABA alone as the preferred rescue
therapy.7
MANDALA,
DENALI and the CREST (Combination
REliever STudies) programme
The CREST clinical trial programme studied the
efficacy and safety of PT027 and included the
MANDALA,1,21,22 DENALI2,23,24 and
TYREE25 Phase
III trials.
MANDALA1,21,22 was
a Phase III, randomised, double-blind, multicentre, parallel-group,
event-driven trial evaluating the efficacy and safety
of Airsupra compared to albuterol on the time to first
severe asthma exacerbation in 3,132 adults, adolescents, and
children (aged 4-11 years) 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: Airsupra 180/160mcg (excluding children aged 4-11
years), albuterol/budesonide 180/80mcg or albuterol 180mcg, taken
as an as-needed rescue medicine. Airsupra and the albuterol comparator were delivered
in a 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 (annualised), asthma control and health-related quality of
life.
Results from the positive MANDALA Phase III trial
showed that Airsupra demonstrated a statistically significant
reduction in the risk of a severe exacerbation versus albuterol
rescue in patients with moderate to severe
asthma.1,22 Compared
with albuterol rescue, Airsupra at the 180mcg albuterol/160mcg budesonide
dose reduced the risk of a severe exacerbation by 27% (p<0.001)
in adults and adolescents.1,22
Primary and secondary endpoint results in adults and
adolescents1,22
(pre-planned on-treatment efficacy analysis)
|
Treatment
Group
|
Comparison
versus albuterol 180mcg
|
|
Time
to first severe exacerbation
|
n
|
Number
(%) of Patients with a Severe Exacerbation a, b
|
Hazard
Ratio(95% CI)
|
p value
(2-sided)
|
|
Airsupra 180/160mcg
|
1013
|
207
(20.4)
|
0.73
(0.61, 0.88)
|
<0.001
|
|
Albuterol
180mcg
|
1014
|
266
(26.2)
|
|
|
Annualised
severe exacerbation rate (rate ratio)
|
n
|
Number
of Severe Exacerbations a, b
|
Annualised
rate(95% CI)
|
Rate
Ratio(95% CI)
|
|
Airsupra 180/160mcg
|
1013
|
334
|
0.45
(0.34, 0.60)
|
0.76
(0.62, 0.93)
|
|
Albuterol
180mcg
|
1014
|
413
|
0.59
(0.44, 0.78)
|
|
|
Annualised
total SCS dose (mg/year)
|
n
|
Mean
(SD) b
|
%
reduction in mean
|
|
Airsupra 180/160mcg
|
1012
|
86.2
(262.86)
|
33.4%
|
|
Albuterol
180mcg
|
1011
|
129.3
(657.19)
|
|
aDeterioration
of asthma requiring use of SCS for ≥3 days, or inpatient
hospitalisation, or emergency room visit, that required
SCS. bBefore
discontinuation of randomised treatment or change in maintenance
therapy.
CI,
confidence interval; SCS, systemic corticosteroid; SD, standard
deviation
Primary endpoint results in adults, adolescents, and
children1,22
(pre-planned on-treatment efficacy analysis)
|
Treatment
Group
|
Comparison
versus albuterol 180mcg
|
|
Time
to first severe exacerbation
|
n
|
Number
(%) of Patients with a Severe Exacerbation a, b
|
Hazard
Ratio(95% CI)
|
p value
(2-sided)
|
|
Albuterol/budesonide
180/80mcg
|
1054
|
241
(22.9)
|
0.83
(0.70, 0.99)
|
0.041
|
|
Albuterol
180mcg
|
1056
|
276
(26.1)
|
|
aDeterioration
of asthma requiring use of SCS for ≥3 days, or inpatient
hospitalisation, or emergency room visit, that required
SCS. bBefore
discontinuation of randomised treatment or change in maintenance
therapy.
CI,
confidence interval
Adverse events (AEs) were similar
across the treatment groups in the trial and consistent with the
known safety profiles of the individual components, with the most
common AEs including nasopharyngitis and
headache.1,22
DENALI2,23,24 was
a Phase III, randomised, double-blind, placebo-controlled,
multicentre, parallel-group trial evaluating the efficacy and
safety of Airsupra compared to its components albuterol and
budesonide on improvement in lung function in 1,001 adults,
adolescents, and children aged 4-11 years 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: Airsupra 180/160mcg four times daily (excluding
children aged 4-11 years), albuterol/budesonide 180/80mcg four
times daily, albuterol 180mcg four times daily, budesonide 160mcg
four times daily (excluding children aged 4-11 years) and placebo
four times daily. Airsupra, the albuterol and budesonide comparators and
placebo were delivered in a pMDI using
AstraZeneca's Aerosphere delivery technology. The dual primary
efficacy endpoints were change from baseline in FEV1 area under the
curve 0-6 hours over 12 weeks of Airsupra compared to budesonide to assess the effect
of albuterol and change from baseline in trough FEV1 at Week 12
of Airsupra 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 1.
In the trial, Airsupra demonstrated 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 in patients with
mild to moderate asthma aged 12 years or older. Onset of action and
duration of effect were similar for Airsupra and albuterol. The safety and tolerability
of Airsupra in DENALI was consistent with the known
profiles of the components.
Airsupra
Airsupra (albuterol/budesonide), formerly known as
PT027, is a first-in-class SABA/ICS rescue treatment for
asthma in the US, to be taken as needed. It is an inhaled,
fixed-dose combination rescue medication containing albuterol (also
known as salbutamol), a SABA, and budesonide, a corticosteroid, and
has been 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 Airsupra 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 Airsupra through NDA filing to a regulatory decision
in the US. Following the successful approval
of Airsupra, AstraZeneca has the option, upon certain
financial payments, to commercialise the medicine in the
US.
AstraZeneca in Respiratory and 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.
References
1. Papi A, et al. Albuterol-Budesonide Fixed-Dose Combination
Rescue Inhaler for Asthma. N Engl J
Med 2022; 386 (22):
2071-2083.
2. Chipps
BE, et
al. Efficacy
and safety of albuterol/budesonide (PT027) in mild-to-moderate
asthma: Results of the DENALI study. Am J Respir
Crit Care Med 2022; 205: A3414. Abstract.
Available at: https://doi.org/10.1164/ajrccm-conference.2022.205.1_MeetingAbstracts.A3414 [Last
accessed: November 2022].
3. The Global Asthma
Network. The Global Asthma Report 2022.
[Online]. Available
at: http://globalasthmareport.org/index.html [Last
accessed: November 2022].
4. CDC. Most Recent
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[Last accessed: November 2022].
5. Yaghoubi
M, et
al.
The Projected Economic and Health Burden of Uncontrolled Asthma in
the United States. Am
J Respir Crit Care Med. 2019; 200 (9):
1102-1112.
6. Airsupra (albuterol/budesonide) US prescribing
information; 2023.
7. Global Initiative
for Asthma. Global strategy for asthma management and prevention,
2022. Available at: https://ginasthma.org/wp-content/uploads/2022/07/GINA-Main-Report-2022-FINAL-22-07-01-WMS.pdf.
[Last accessed: November 2022].
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asthma. J Allergy Clin Immunol
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1989-98.e3.
10.
AstraZeneca Pharmaceuticals. Data on File. Budesonide/formoterol
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(REF-173201)
11. 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.
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asthma. J Bras
Pneumol. 2014; 40 (4):
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13. Wark PA, et al. Asthma exacerbations· 3:
pathogenesis. Thorax. 2006; 61 (10): 909-15.
14. Johnson DB, et al. Albuterol. 2022 May 1. In: StatPearls
[Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
PMID: 29489143.
15. Montemayor T, et al. Albuterol: Often Used and Heavily
Abused. Respiratory
Care November
2021, 66 (Suppl 10) 3603775.
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Albuterol: Drug Usage Statistics, US 2013 - 2020. Available
at: https://clincalc.com/DrugStats/Drugs/Albuterol.
[Last accessed: November 2022].
17. 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
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1901872.
18. 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
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19. Bourdin A, et al. ERS/EAACI statement on severe exacerbations in
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20. Price DB, et al. Adverse outcomes from initiation of systemic
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21. 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
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22. Papi
A, et
al. Efficacy
and safety of as-needed albuterol/budesonide versus as-needed
albuterol in adults, adolescents and children aged ≥4 years with
moderate-to-severe asthma: Results of the MANDALA study. American
Thoracic Society International Conference 2022. Oral Presentation.
Abstract A3413 during B93.
BREAKTHROUGHS IN PEDIATRIC AND ADULT ASTHMA CLINICAL
TRIALS.
23. Clinicaltrials.gov. A
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Metered-dose Inhaler (BDA MDI/PT027) Used 4 Times Daily in Adults
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Available at https://clinicaltrials.gov/ct2/show/NCT03847896.
[Last accessed: November 2022].
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AstraZeneca Pharmaceuticals. Data on File. DENALI clinical trial
protocol Data on File (ID: 121792).
25. LaForce
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169-177.
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:
11 January 2023
|
|
By: /s/
Adrian Kemp
|
|
|
Name:
Adrian Kemp
|
|
|
Title:
Company Secretary
|
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