World-First Results In Continued Exploration Of Combination 2 In 1 ‘Rescue’ Inhaler

A fixed-dose 2 in 1 combination of salbutamol and budesonide, used as an as-needed rescue medicine, has been shown for the first time to significantly reduce the risk of severe asthma attacks.

In the MANDALA trial, patients using the investigational AstraZeneca and Avillion product PT027, which combines salbutamol (marketed as albuterol within the U.S.) with budesonide, were 26% less likely to experience severe asthma attacks than those using albuterol alone.

These findings were reported by lead author Professor Alberto Papi, of the University of Ferrara in Italy, and colleagues, including Professor Richard Beasley, director of the Medical Research Institute of New Zealand (MRINZ), published in the New England Journal of Medicine on Sunday 15 May, and presented this week at the American Thoracic Society (ATS) 2022 International Conference.

Asthma is a chronic respiratory disease that affects more than 330 million adults and children worldwide, including over 610,000 in Aotearoa New Zealand, where we have one of the highest rates of asthma in the world. Reducing the risk of asthma attacks is the number one priority for the management of asthma in New Zealand and internationally. As a result, the findings from the MANDALA trial are of both local and global importance. 
 

In asthma, inflammation of the airways in the lungs is central to both symptoms and asthma attacks. For more than 50 years, people with asthma were prescribed a short-acting beta2-agonist reliever inhaler such as salbutamol as the first-line treatment for symptom relief. However, while these reliever asthma inhalers are effective in reducing acute symptoms, they do nothing to alleviate the underlying inflammation responsible for those symptoms, leaving patients at risk of severe attacks, which can be life-threatening, resulting in hospitalisation and risk of death.
 

The idea behind the 2 in 1 combination reliever therapy approach is that by adding an anti-inflammatory preventer medication to the reliever inhaler, it allows the patient to self-titrate the dose of the preventer medication according to their changing needs, directly treating the underlying increase in airways inflammation that causes worsening symptoms. 
 

Over the last decade, the 2 in 1 combination reliever therapy approach has been established in clinical practice worldwide with a different combination of the fast-onset and longer acting beta2-agonist formoterol with the preventer medication budesonide.
 

Landmark clinical trials undertaken by Professor Richard Beasley and the research team at the MRINZ have shown that a 2 in 1 inhaler containing budesonide and formoterol, is far more effective than the traditional single reliever inhaler such as salbutamol or terbutaline. These MRINZ studies have contributed to the evidence on which the Asthma and Respiratory Foundation of New Zealand adolescent and adult asthma guidelines recommend budesonide-formoterol, rather than salbutamol, as the preferred reliever medication, across the range of asthma severity.

Professor Richard Beasley, MRINZ director and MANDALA study co-author says, "The latest findings are of major clinical importance, as they provide further evidence that the 2 in 1 reliever therapy approach is superior to the historical single reliever therapy approach with medications such as salbutamol. Furthermore, it means there will soon be alternative products available for the 2 in 1 reliever therapy approach, with some doctors and patients likely to prefer the budesonide-salbutamol inhaler to the budesonide-formoterol inhaler.”

“The combined 2 in 1 inhaler reliever therapy approach is considered the biggest paradigm advance in the management of asthma for decades. Its widespread implementation in clinical practice provides a real opportunity to reduce the enormous global health burden from asthma,” says Professor Beasley.

ENDS

KEY POINTS AT A GLANCE

PT027, a fixed-dose combination of albuterol (also known as salbutamol) and budesonide, used as an as-needed rescue medicine, has been shown to significantly reduce the risk of a severe asthma attack by 26%, compared to albuterol alone.

As asthma symptoms worsen, patients have typically relied on short-acting beta2-agonist rescue therapy, but this treatment does not address worsening inflammation, which leaves patients at risk for severe asthma attacks, which can result in impaired quality of life, hospitalisation, increased use of systemic steroids, and at times, death.
 

Previous MRINZ studies have shown that a 2 in 1 inhaler, containing both the inhaled corticosteroid budesonide, together with the fast but long-acting beta2-agonist reliever formoterol, is far more effective than traditional single reliever inhalers such as salbutamol or terbutaline.
 

The results of the 'Albuterol–Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma ' MANDALA study were published in the New England Journal of Medicine on Sunday 15 May and presented at the American Thoracic Society (ATS) 2022 International Conference, May 13-17. The paper was authored by Alberto Papi, M.D., Bradley E. Chipps, M.D., Richard Beasley, D.Sc., Reynold A. Panettieri, Jr., M.D., Elliot Israel, M.D., Mark Cooper, M.Sc., Lynn Dunsire, M.Sc., Allison Jeynes-Ellis, M.D., Eva Johnsson, M.D., Robert Rees, Ph.D., Christy Cappelletti, Pharm.D., and Frank C. Albers, M.D.

Professor Richard Beasley’s contribution to the MANDALA study publication highlights the ongoing impact the MRINZ has on investigating novel treatment approaches that have the real potential to reduce the burden of severe attacks in asthma.

BACKGROUND TRIAL DETAIL

Papi A, et al. Albuterol-budesonide fixed-dose combination rescue inhaler for asthma. N Eng J Med. 2022; May 15. DOI: 10.1056/NEJMoa2203163

MANDALA was a Phase III, double-blind, randomised, event-driven trial to evaluate the efficacy and safety of albuterol–budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial. 
 

Adults and adolescents (12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: a fixed-dose combination of 180 g of albuterol and 160 g of budesonide (with each dose consisting of two actuations of 90 g and 80 g, respectively [the higher-dose combination group]), a fixed-dose combination of 180 g of albuterol and 80 g of budesonide (with each dose consisting of two actuations of 90 g and 40 g, respectively [the lower-dose combination group]), or 180 g of albuterol (with each dose consisting of two actuations of 90 g [the albuterol-alone group]). Children 4 to 11 years of age were randomly assigned to only the lower-dose combination group or the albuterol-alone group. The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population.

A total of 3132 patients underwent randomisation, among whom 97% were 12 years of age or older. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group than in the albuterol-alone group (hazard ratio, 0.74; 95% confidence interval [CI], 0.62 to 0.89; P=0.001). The hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, was 0.84 (95% CI, 0.71 to 1.00; P=0.052). The incidence of adverse events was similar in the three trial groups.

The risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 g of albuterol and 160 g of budesonide than with as-needed use of albuterol alone among patients with uncontrolled moderate-to-severe asthma who were receiving a wide range of inhaled glucocorticoid-containing maintenance therapies. (Funded by Avillion; MANDALA ClinicalTrials.gov number, NCT03769090.)

Medical Research Institute of New Zealand 
 

Rangahautia Te Ora 
 

The Medical Research Institute of New Zealand (MRINZ) is Aotearoa New Zealand’s leading independent medical research institute. MRINZ research is guided by a simple philosophy: it must challenge dogma, increase knowledge, and have the potential to improve clinical practice and outcomes, both in Aotearoa New Zealand, and internationally.

The MRINZ’s research teams are dedicated to investigating important public health problems, delivering high quality evidence on which to improve the management of disease and patient care. An internationally recognised academic institution, the MRINZ operates under a charitable trust pursuing advances in clinical practice and providing a base for specialist training in medical research. The MRINZ is committed to contributing toward a more equitable society that celebrates Te Ao Māori and upholds Te Tiriti o Waitangi.

MRINZ-led research has changed the way the world manages asthma. MRINZ research teams investigate novel approaches to the management and prevention of asthma, to best determine how to reduce the risk of developing this common disease, and how it is most effectively treated.

Professor Richard Beasley, MRINZ Director 
Richard Beasley, MBChB, MD, DSc, CNZM, is a physician at Wellington Regional Hospital, Director of the Medical Research Institute of New Zealand, and Professor of Medicine at Victoria University of Wellington. He is an Adjunct Professor at the University of Otago and Visiting Professor, University of Southampton, United Kingdom. He was previously the Deputy Chair of the Health Research Council of New Zealand. His research interests in respiratory medicine are primarily in the fields of epidemiology and clinical management. 
 

Professor Beasley is available for interview.

MEDIA ENQURIES

Nicola Marshall, MRINZ Communications Advisor 
Nicola.Marshall@mrinz.ac.nz 
+64 21 256 4737

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