First time an albuterol/budesonide
fixed-dose combination rescue medication has been shown to reduce
severe exacerbations
MANDALA Phase III trial results published in
the New England Journal of Medicine and presented at ATS 2022
International Conference
Full results from the positive MANDALA Phase III trial showed
that PT027 (albuterol/budesonide) at two different strengths of
budesonide, an inhaled corticosteroid (ICS), used as an as-needed
rescue medicine, demonstrated a statistically significant reduction
in the risk of a severe exacerbation versus albuterol rescue in
patients with moderate to severe asthma.1,2
PT027 is a potential first-in-class inhaled, fixed-dose
combination rescue medication containing albuterol, a short-acting
beta2-agonist (SABA), and budesonide in the US. It is being
developed by AstraZeneca and Avillion.
Globally, more than 176 million asthma attacks are experienced
each year.3
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.1,2 In
the trial, patients were randomized to receive PT027 or albuterol
rescue, on top of their usually prescribed maintenance ICS, with or
without additional controller medicines.1,2
In secondary endpoints, PT027 (180mcg albuterol/160mcg
budesonide) demonstrated a 33% reduction in mean annualized total
systemic corticosteroid exposure (p=0.002) and a 24% reduction in
annualized severe exacerbation rate (p=0.008).1,2 A numerically
higher odds of patients experiencing an improvement in symptom
control and quality of life was also observed after 24 weeks of
treatment with PT027 compared to albuterol rescue.1,2
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
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:
“The MANDALA Phase III trial results demonstrated that PT027, a
novel fixed-dose combination of albuterol/budesonide used
as-needed, provided additional anti-inflammatory treatment in
response to patient symptoms, which led to a reduced risk of severe
exacerbations compared with albuterol alone. These data further
strengthen the growing body of evidence around the value of
as-needed anti-inflammatory treatment in asthma and support PT027’s
potential to transform the current rescue treatment approach.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals
R&D, AstraZeneca, said: “Asthma is an inflammatory, variable
disease and patients are at risk of experiencing a severe
exacerbation regardless of disease severity and adherence to
treatment. The results from these Phase III trials support the
clinical benefit of PT027, an albuterol/budesonide rescue inhaler,
which has the potential to be a first-in-class treatment approach
that can prevent asthma attacks over and above their current
maintenance therapies.”
In the MANDALA trial, PT027 at a lower budesonide dose (180mcg
albuterol/80mcg budesonide), also demonstrated a statistically
significant reduction of 17% in the risk of severe exacerbation
versus albuterol rescue (p=0.041), when used as an as-needed rescue
medicine in adults, adolescents, and children aged 4–11
years.1,2
The results were published in the New
England Journal of Medicine and will be presented at the
American Thoracic Society (ATS) 2022 International
Conference.1,2,4
Also being presented at the ATS International Conference this
week are the positive DENALI Phase III trial results. In this
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.5
Notes
Asthma
Asthma is a chronic, inflammatory, variable respiratory disease
that affects as many as 339 million adults and children worldwide,6
including over 25 million in the US.7
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;7 these are
physically threatening and emotionally significant for many
patients11 and can be fatal.6,12
Inflammation is central to both asthma symptoms8 and
exacerbations.13 Many patients experiencing asthma symptoms use a
SABA as a rescue medicine; however, taking a SABA alone does not
address inflammation, leaving patients at risk of severe
exacerbations,14 which can result in impaired quality of life,15
hospitalization16 and frequent oral corticosteroid (OCS) use.16
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.8,17,18
International recommendations from the Global Initiative for Asthma
no longer recommend SABA alone as the preferred rescue
therapy.8
MANDALA
MANDALA1,19 was a Phase III, randomized, double-blind,
multicenter, parallel-group, event-driven trial evaluating the
efficacy and safety of PT027 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: 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 pressurized 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 (annualized), total systemic
corticosteroid exposure (annualized), asthma control and
health-related quality of life.
Primary and secondary endpoint
results in adults and adolescents1,2
(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)
Annualized total SCS dose
(mg/year)
n
Mean (SD) b
% reduction in mean
PT027 180/160mcg
1012
86.2 (262.86)
33.4%
Albuterol 180mcg
1011
129.3 (657.19)
Annualized severe exacerbation
rate (rate ratio)
n
Number of Severe
Exacerbations a, b
Annualized 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)
aDeterioration of asthma
requiring use of SCS for ≥3 days, or inpatient hospitalization, or
emergency room visit, that required SCS. bBefore discontinuation of
randomized treatment or change in maintenance therapy.
CI, confidence interval; SCS,
systemic corticosteroid; SD, standard deviation
Primary endpoint results in
adults, adolescents, and children1,2
(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 180/80mcg
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 hospitalization, or
emergency room visit, that required SCS. bBefore discontinuation of
randomized treatment or change in maintenance therapy.
CI, confidence interval
DENALI
DENALI4,20,21 was a Phase III, randomized, double-blind,
placebo-controlled, multicenter, 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, number of patients who achieved a clinically
meaningful improvement in asthma control from baseline at Week 12
and trough FEV1 at Week 1.
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 program for the
treatment of asthma. Under the terms of the agreement, Avillion
became the trial sponsor responsible for executing and funding the
multicenter, global clinical trial program 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 commercialize the medicine in the US.
AstraZeneca in Respiratory & 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.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialization 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. For more
information, please visit www.astrazeneca-us.com and follow us on
Twitter @AstraZenecaUS.
©2022 AstraZeneca. All rights reserved. Used with
permission.
References
- Papi A, et al. Albuterol-budesonide fixed-dose combination
rescue inhaler for asthma. N Eng J Med. 2022; May 15. DOI:
10.1056/NEJMoa2203163. Online ahead of print.
- 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.
- AstraZeneca Pharmaceuticals. Data on File.
Budesonide/formoterol Data on File: Annual Rate of Asthma
Exacerbations Globally. (ID: SD-3010-ALL-0017).
- Papi A, et al. Albuterol-Budesonide Fixed-Dose Combination
Rescue Inhaler in Patients with Asthma. JAMA and The New England
Journal of Medicine. Discussion on the edge: reports of recently
published pulmonary research. American Thoracic Society
International Conference 2022. Presentation.
- Chipps BE, et al. Efficacy and safety of albuterol/budesonide
(PT027) in mild-to-moderate asthma: Results of the DENALI study.
American Thoracic Society International Conference 2022. Abstract.
Available at:
https://www.abstractsonline.com/pp8/#!/10476/presentation/7832
[Last accessed 15 May 2022].
- The Global Asthma Network. The Global Asthma Report 2018.
[Online]. Available at:
http://globalasthmareport.org/resources/Global_Asthma_Report_2018.pdf.
[Last accessed: 4 May 2022].
- CDC. Most Recent National Asthma Data. [Online]/ Available at:
https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm.
[Last accessed: 4 May 2022].
- Global Initiative for Asthma. 2021 GINA Report, Global Strategy
for Asthma Management and Prevention. [Online]. Available at:
https://ginasthma.org/wp-content/uploads/2021/04/GINA-2021-Main-Report_FINAL_21_04_28-WMS.pdf
[Last accessed: 4 May 2022]
- 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.
- 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.
- 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.
- Fernandes AG, et al. Risk factors for death in patients with
severe asthma. J Bras Pneumol. 2014; 40 (4): 364-372
- Wark PA, et al. Asthma exacerbations· 3: pathogenesis. Thorax.
2006; 61 (10): 909-15.
- Nwaru BI, et al. Overuse of short-acting β2-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.
- 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.
- Bourdin A, et al. ERS/EAACI statement on severe exacerbations
in asthma in adults: facts, priorities and key research questions.
Eur Respir J. 2019; 54 (3): 1900900.
- Price DB, et al. Adverse outcomes from initiation of systemic
corticosteroids for asthma: long-term observational study. J Asthma
Allergy. 2018; 11: 193–204.
- 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: 4 May 2022].
- 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.
- 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: 4
May 2022].
- AstraZeneca Pharmaceuticals. Data on File. DENALI clinical
trial protocol Data on File (ID: 121792).
Last Updated 5/22
View source
version on businesswire.com: https://www.businesswire.com/news/home/20220515005046/en/
Media Inquiries Brendan McEvoy +1 302 885 2677
Jillian Gonzales +1 302 885 2677
US Media Mailbox: usmediateam@astrazeneca.com
AstraZeneca (NASDAQ:AZN)
Historical Stock Chart
Von Jun 2024 bis Jul 2024
AstraZeneca (NASDAQ:AZN)
Historical Stock Chart
Von Jul 2023 bis Jul 2024