a8048f
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
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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,
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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
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asthma: Results of the DENALI study. Am J Respir
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for Asthma. Global strategy for asthma management and prevention,
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[Last accessed: 11 October 2022].
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patients: the REcognise Asthma and LInk to Symptoms and Experience
(REALISE) survey. NPJ Prim Care Respir
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to asthma exacerbations in patients with moderate-to-severe
asthma. J Allergy Clin Immunol
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11. Sastre J, et al. Insights, attitudes, and perceptions about
asthma and its treatment: a multinational survey of patients from
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asthma. J Bras
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[Internet]. Treasure Island (FL): StatPearls Publishing; 2022
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Abused. Respiratory
Care October
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[Last accessed: 11 October 2022].
17. Nwaru BI, et al. Overuse of short-acting b2-agonists in asthma is
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[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
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[Last accessed: 11 October 2022].
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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
|