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 November 2022
Commission File
Number: 001-11960
AstraZeneca
PLC
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AstraZeneca
PLC
INDEX
TO EXHIBITS
1.
FDA Advisory Committee recommends PT027 in asthma
9
November 2022 07:00 GMT
PT027 recommended by FDA advisory committee as new rescue treatment
for asthma
First and only rescue medication recommended for US approval that
has been shown to reduce severe exacerbations
The
Food and Drug Administration's (FDA) Pulmonary-Allergy Drugs
Advisory Committee (PADAC) has voted 16 to 1 that the data support
a favourable benefit risk assessment for the use of PT027
(albuterol/budesonide) for the treatment of asthma in people aged
18 years and older. In adolescents aged 12 to 17 years, the
Committee voted 9 to 8 that the data do not support a favourable
benefit risk assessment for the use of PT027 for the treatment of
asthma. In children aged 4 to 11 years, the Committee voted 16 to 1
that the data do not support a favourable benefit risk assessment
for the use of PT027 for the treatment of
asthma.
PT027
is a potential first-in-class, pressurised metered-dose inhaler
(pMDI), fixed-dose combination rescue medication in the US
containing albuterol, a short-acting beta2-agonist (SABA), and
budesonide, an anti-inflammatory inhaled corticosteroid (ICS). It
is being developed by AstraZeneca and Avillion.
In
the first half of 2022, the FDA accepted the New Drug Application
(NDA) for PT027 and set a Prescription Drug User Fee Act date for
the first half of 2023.
Bradley
E. Chipps, Past President of the American College of Allergy,
Asthma & Immunology and Medical Director of the Capital Allergy
& Respiratory Disease Center in Sacramento, US, said: "Millions
of people with asthma rely on their albuterol rescue inhaler to
alleviate acute symptoms, but this does not treat the underlying
inflammation, leaving patients at risk of severe asthma
exacerbations, regardless of their disease severity or level of
control. If approved, PT027 could transform the current rescue
treatment approach."
Mene
Pangalos, Executive Vice President, BioPharmaceuticals R&D,
AstraZeneca, said: "We are pleased that the Pulmonary-Allergy Drugs
Advisory Committee has recognised the potential for PT027 to
deliver important benefits for people with asthma, as a
first-in-class treatment option in the US. We look forward to
working with our partner Avillion and the FDA to progress the
application and discuss next steps, including for adolescents and
children."
Asthma is a chronic, inflammatory, variable
respiratory disease that affects as many as 339 million people
worldwide,1 including
over 25 million in the US.2 Globally,
more than 176 million asthma attacks are experienced each
year.3
The NDA submission was based on results from the
MANDALA, DENALI and TYREE Phase III trials.4-7 In
MANDALA, PT027 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.4,5 In
DENALI, PT027 significantly improved lung function compared to the
individual components, albuterol and budesonide, in patients with
mild to moderate asthma.6
The safety and tolerability of PT027 in these
trials were consistent with the known profiles of the
components.4-7
Results from the MANDALA trial were published in
the New
England Journal of Medicine in May 2022.4
PADAC
reviews and evaluates available data concerning the safety and
effectiveness of marketed and investigational human drug
products for use in the treatment of pulmonary disease and diseases
with allergic and/or immunologic mechanisms and makes appropriate
recommendations to the Commissioner of Food and Drugs.
Notes
Asthma
Asthma is a chronic, inflammatory, variable
respiratory disease that affects as many as 339 million adults and
children worldwide,1 including
over 25 million in the US.2
Patients with asthma experience recurrent
breathlessness and wheezing, which varies over time, and in
severity and frequency.8 These
patients are at risk of severe exacerbations regardless of their
disease severity, adherence to treatment or level of
control.9,10
There are an estimated 176 million asthma
exacerbations globally per year,3 including
more than 10 million in the US;2 these
are physically threatening and emotionally significant for many
patients11 and
can be fatal.1,12
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 1-2 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.8,20,21 International
recommendations from the Global Initiative for Asthma no longer
recommend SABA alone as the preferred rescue
therapy.8
MANDALA
MANDALA4,22 was
a Phase III, randomised, double-blind, multicentre, parallel-group,
event-driven trial evaluating the efficacy and safety of PT027
compared to albuterol on the risk of experiencing a 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: PT027 180/160mcg
(excluding children aged 4-11 years), PT027 180/80mcg or albuterol
180mcg, taken as an as-needed rescue medicine. 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 (annualised), asthma control and health-related quality of
life.
Full results from the positive MANDALA Phase III
trial showed that PT027 (albuterol/budesonide) demonstrated a
statistically significant reduction in the risk of a severe
exacerbation versus albuterol rescue in patients with moderate to
severe asthma. Compared with albuterol rescue, PT027 at the 180mcg
albuterol/160mcg budesonide dose reduced the risk of a severe
exacerbation by 27% (p<0.001) in adults and
adolescents.4,5
Primary and secondary endpoint results in adults and
adolescents4,5
(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)
|
|
PT027
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)
|
|
PT027
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
|
p-valuec (2-sided) c
|
|
PT027
180/160mcg
|
1012
|
86.2
(262.86)
|
33.4%
|
0.002
|
|
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. cWilcoxon
rank sum test
CI,
confidence interval; SCS, systemic corticosteroid; SD, standard
deviation
Primary endpoint results in adults, adolescents, and
children4,5
|
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)
|
|
PT027
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 were consistent with
the known safety profiles of the individual components, with the
most common AEs including nasopharyngitis and
headache.4,5
DENALI
DENALI6,23,24 was
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,
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: PT027
180/160mcg four times daily (excluding children aged 4-11 years),
PT027 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. PT027, 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 PT027 compared to budesonide to
assess the effect of albuterol and 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, the 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, PT027 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 PT027 and albuterol. The safety
and tolerability of PT027 in DENALI was consistent with the known
profiles of the components.
PT027
PT027 is a potential 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 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 NDA
filing to a 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 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. The Global Asthma
Network. The Global Asthma Report 2018. [Online]. Available
at: http://www.globalasthmareport.org.
[Last accessed: 11 October 2022].
2. CDC. Most Recent
National Asthma Data. [Online]/ Available at: https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm.
[Last accessed: 11 October 2022].
3.
AstraZeneca Pharmaceuticals. Data on File. Budesonide/formoterol
Data on File: Annual Rate of Asthma Exacerbations Globally. (ID:
SD-3010-ALL-0017).
4. Papi A, et al. Albuterol-Budesonide Fixed-Dose Combination
Rescue Inhaler for Asthma. N Engl J
Med 2022; 386 (22):
2071-2083.
5. 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 PAEDIATRIC AND
ADULT ASTHMA CLINICAL TRIALS
6. 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: 11 October 2022].
7. LaForce C, et al. Albuterol/budesonide for the treatment of
exercise-induced bronchoconstriction in patients with asthma: The
TYREE study. Ann Allergy Asthma
Immunol. 2022; 128:
169-177.
8. 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: 11 October 2022].
9. 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.
10. 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.
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.
15. Montemayor T, et al. Albuterol: Often Used and Heavily
Abused. Respiratory
Care October
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: 11 October 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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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
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193-204.
21. EPR-3: Expert panel
report 3. Guidelines for the Diagnosis and Management of Asthma
2007 (EPR-3). [Online]. Available at: https://www.nhlbi.nih.gov/health-topics/guidelines-for-diagnosis-management-of-asthma.
[Last accessed: 11 October 2022].
22. 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.
23. Clinicaltrials.gov. A
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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: 11 October 2022].
24.
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 November 2022
|
|
By: /s/
Adrian Kemp
|
|
|
Name:
Adrian Kemp
|
|
|
Title:
Company Secretary
|
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