TIDMAZN
RNS Number : 8048F
AstraZeneca PLC
09 November 2022
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
patients(11) and can be fatal.(1,12)
Inflammation is central to both asthma symptoms(8) 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) hospitalisation(19) 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
MANDALA(4,22) 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
adolescents(4,5)
(pre-planned on-treatment efficacy analysis)
Treatment Group Comparison versus albuterol 180mcg
---------------------------------------------
Time to first severe n Number (%) of Patients with a Hazard Ratio p value (2--sided)
exacerbation Severe Exacerbation (a, b) (95% CI)
---- ------------------------------- ------------------- ------------------------
PT027 180/160mcg 1013 207 (20.4) 0.73 (0.61, 0.88) <0.001
---- ------------------------------- ------------------- ------------------------
Albuterol 180mcg 1014 266 (26.2)
---- ------------------------------- ---------------------------------------------
Annualised severe exacerbation n Number of Severe Exacerbations Annualised rate Rate Ratio
rate (rate ratio) (a, b) (95% CI) (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 n Mean (SD) (b) % reduction in mean p-value(c) (2-sided) (c)
(mg/year)
---- ------------------------------- ------------------- ------------------------
PT027 180/160mcg 1012 86.2 (262.86) 33.4% 0.002
---- ------------------------------- ------------------- ------------------------
Albuterol 180mcg 1011 129.3 (657.19)
---- ------------------------------- ---------------------------------------------
(a) Deterioration of asthma requiring use of SCS for >=3
days, or inpatient hospitalisation, or emergency room visit, that
required SCS. (b) Before discontinuation of randomised treatment or
change in maintenance therapy. (c) Wilcoxon rank sum test
CI, confidence interval; SCS, systemic corticosteroid; SD,
standard deviation
Primary endpoint results in adults, adolescents, and
children(4,5)
Treatment Group Comparison versus albuterol 180mcg
-------------------------------------
Time to first severe exacerbation n Number (%) of Patients with a Severe Hazard Ratio p value (2--sided)
Exacerbation (a, b) (95% CI)
---- ------------------------------------- ----------------- ------------------
PT027 180/80mcg 1054 241 (22.9) 0.83 (0.70, 0.99) 0.041
---- ------------------------------------- ----------------- ------------------
Albuterol 180mcg 1056 276 (26.1)
---- ------------------------------------- -------------------------------------
(a) Deterioration of asthma requiring use of SCS for >=3
days, or inpatient hospitalisation, or emergency room visit, that
required SCS. (b) Before 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
DENALI(6,23,24) 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].
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exercise-induced bronchoconstriction in patients with asthma: The
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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].
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moderate-to-severe asthma. J Allergy Clin Immunol Pract. 2018; 6
(6): 1989-98.e3.
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asthma and its treatment: a multinational survey of patients from
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Thorax. 2006; 61 (10): 909-15.
14. Johnson DB, et al. Albuterol. 2022 May 1. In: StatPearls
[Internet]. Treasure Island (FL): StatPearls Publishing; 2022
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Abused. Respiratory Care October 2021, 66 (Suppl 10) 3603775
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. [Last accessed: 11 October 2022].
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<BETA>2-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.
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health-related quality of life in moderate to severe asthma
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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.
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Safety of Budesonide/Albuterol Metered-dose Inhaler (BDA MDI/PT027)
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11 October 2022].
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trial protocol Data on File (ID: 121792).
Adrian Kemp
Company Secretary
AstraZeneca PLC
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