REG - AstraZeneca PLC - FDA Advisory Committee recommends PT027 in asthma

AstraZenecaAnnouncement

09/11/2022 07:00

For best results when printing this announcement, please click on link below:
http://newsfile.refinitiv.com/getnewsfile/v1/story?guid=urn:newsml:reuters.com:20221109:nRSI8048Fa&default-theme=true

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 (https://www.nejm.org/doi/full/10.1056/NEJMoa2203163) 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 exacerbation                 n       Number (%) of Patients with a Severe Exacerbation (a, b)  Hazard Ratio         p value (2‑sided)

(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 rate (rate ratio)  n       Number of Severe Exacerbations (a, b)                     Annualised rate      Rate Ratio

(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 (mg/year)               n       Mean (SD) (b)                                             % reduction in mean  p-value(c) (2-sided) (c)
 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 Exacerbation (a, b)  Hazard Ratio        p value (2‑sided)

(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
(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
(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
(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
(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
(https://clincalc.com/DrugStats/Drugs/Albuterol) . [Last accessed: 11 October
2022].

17.  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.

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 J. 2019;
54 (3): 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.  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
(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 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
(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

 

 

This information is provided by RNS, the news service of the London Stock Exchange. RNS is approved by the Financial Conduct Authority to act as a Primary Information Provider in the United Kingdom. Terms and conditions relating to the use and distribution of this information may apply. For further information, please contact
rns@lseg.com (mailto:rns@lseg.com)
 or visit
www.rns.com (http://www.rns.com/)
.

RNS may use your IP address to confirm compliance with the terms and conditions, to analyse how you engage with the information contained in this communication, and to share such analysis on an anonymised basis with others as part of our commercial services. For further information about how RNS and the London Stock Exchange use the personal data you provide us, please see our
Privacy Policy (https://www.lseg.com/privacy-and-cookie-policy)
.   END  MSCFIFLRLFLAIIF