Fixed-dose albuterol-budesonide rescue inhaler cuts severe asthma attack risk: MANDALA
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SAN FRANCISCO — In patients with uncontrolled moderate to severe asthma, a fixed-dose combination of albuterol and budesonide used as an as-needed rescue medication lowered risk for severe asthma exacerbations compared with albuterol alone.
“MANDALA met its primary endpoint: Albuterol-budesonide significantly reduced exacerbation risk vs. albuterol,” Alberto Papi, MD, professor of respiratory medicine at University of Ferrara Medical School in Italy, said during a presentation of the findings at the American Thoracic Society International Conference. Results were simultaneously published in The New England Journal of Medicine.
In a preplanned efficacy analysis, the primary endpoint of time to first severe asthma exacerbation was 27% lower among patients assigned a fixed-dose combination of albuterol 180 µg and budesonide 160 µg compared with albuterol 180 µg alone (HR = 0.73; 95% CI, 0.61-0.88; P < .001) and 17% lower with a lower-dose combination of albuterol 180 µg and budesonide 80 µg (HR = 0.83; 95% CI, 0.7-0.99; P = .041). In an intention-to-treat analysis, risk was reduced by 26% with the higher-dose combination (HR = 0.74; 95% CI, 0.62-0.89; P = .001) and 16% with the lower-dose combination (HR = 0.84; 95% CI, 0.71-1; P = .052), Papi said during the presentation.
The study treatment, PT027, is a potential first-in class inhaled, fixed-dose combination rescue medication containing the short-acting beta 2 agonist albuterol and the inhaled corticosteroid budesonide in the U.S. It is being developed by AstraZeneca and Avillion, according to a company press release.
The fixed-dose combination rescue inhaler was developed to provide rapid relief of asthma symptoms and simultaneously treat the variability of underlying inflammation when needed most, according to Papi.
“Albuterol by itself, although it works initially with good bronchodilatation, does not affect the inflammatory component of asthma and as a result does not prevent exacerbations. We know one-third to 45% of patients with mild asthma exacerbate every year. We need to intervene in the ‘window of opportunity,’ which is when asthma control lessens when people become more symptomatic to prevent their progression to an exacerbation,” Bradley E. Chipps, MD, past president of the American College of Allergy, Asthma and Immunology and medical director of the Capital Allergy & Respiratory Disease Center in Sacramento, California, told Healio. The take-home message of this trial is: “You can keep your patients from having to take oral corticosteroids. No matter what you think your patients do, many don’t take their medications; they view asthma as an episodic disease. This [fixed-dose combination rescue inhaler] helps to stop episodic increases in symptoms prior to progressing to an exacerbation,” Chipps said.
The phase 3, double-blind, randomized, event-driven trial enrolled symptomatic patients aged 4 years and older with moderate to severe asthma and at least one severe exacerbation in the prior year. The mean age was about 49 years, two-thirds were female and 81% were white. A total of 3,132 patients were randomly assigned to the higher-dose group, lower-dose group or albuterol only; of those, only 183 were aged 4 years to younger than 18 years. The study medication was administered via pressurized metered-dose inhaler in two actuations. All patients were receiving maintenance inhaled corticosteroids alone or combined with other controller medications.
The fixed-dose combination also reduced mean annualized total systemic corticosteroid exposure and the annualized severe exacerbation rate, according to the NEJM publication. Researchers reported numerically higher odds of improvement in symptom control and quality of life with the fixed-dose combination.
The incidence of any adverse event was similar across the three groups, at 46.2% in the higher-dose combination group, 47.1% in the lower-dose combination group and 46.4% in the albuterol-only group. Serious adverse events occurred in 5.2%, 3.8% and 4.5%, respectively. Adverse events were consistent with the known safety profiles of the individual components; the most common adverse events were nasopharyngitis, headache and upper respiratory tract infection.
“Given the efficacy of adding budesonide to albuterol as a rescue medication and the duration of the treatment, we believe that this is going to be potentially a change in the paradigm of the use of rescue medication,” Papi said.
Three phase 3 studies evaluating albuterol-budesonide fixed-dose combination as pressurized meter-dose inhaler in patients with asthma are now completed: TYREE, MANDALA and DENALI. DENALI will be presented at a later date during the ATS International Conference; this article will be updated.
References:
- Papi A, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2203163.
- PT027, a novel fixed-dose combination of albuterol and budesonide, used as an as-needed rescue medication, significantly reduced the risk of a severe exacerbation compared to albuterol by 27% in patients with asthma. Published May 15, 2022. Accessed May 15, 2022.
- Avillion announces publication of positive full results from MANDALA phase III trial of AstraZeneca’s PT027 in asthma patients in the New England Journal of Medicine. Published May 15, 2022. Accessed May 15, 2022.