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
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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
National Asthma Data. [Online]/ Available at: https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm.
[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].
8. 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.
9. Papi A, 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.
10.
AstraZeneca Pharmaceuticals. Data on File. Budesonide/formoterol
Data on File: Annual Rate of Asthma Exacerbations Globally.
(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.
12. Fernandes AG, et al. Risk factors for death in patients with severe
asthma. J Bras
Pneumol. 2014; 40 (4):
364-372.
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.
16. ClinCalc.com.
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
J. 2020; 55 (4):
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
J. 2007; 16 (1):
22-7.
19. Bourdin A, et al. ERS/EAACI statement on severe exacerbations in
asthma in adults: facts, priorities and key research
questions. Eur Respir
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1900900.
20. Price DB, et al. Adverse outcomes from initiation of systemic
corticosteroids for asthma: long-term observational
study. J Asthma
Allergy. 2018; 11:
193-204.
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
Study. Am J Respir Crit Care
Med. 2020; 201:
A3015.
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
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: November 2022].
24.
AstraZeneca Pharmaceuticals. Data on File. DENALI clinical trial
protocol Data on File (ID: 121792).
25. LaForce
C, et
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Albuterol/budesonide for the treatment of exercise-induced
bronchoconstriction in patients with asthma: The TYREE study. Ann
Allergy Asthma Immunol. 2022; 128:
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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