ATS: Rescue Combo Fixed-Dose Albuterol-Budesonide Reduces Asthma Exacerbations

As-needed use of a fixed-dose combination albuterol-budesonide therapy proved more effective for reducing the risk for severe exacerbations than rescue albuterol alone in patients with uncontrolled asthma enrolled in the phase III MANDALA multinational randomized clinical trial.

When given to patients also taking inhaled corticosteroids (ICS), with or without additional controller medications, the investigational fixed dose treatment PTO27 reduced the risk for severe exacerbations by 26% (P<0.001), compared to albuterol alone, among patients with moderate-to-severe asthma.

Peer-reviewed study findings were published Sunday in The New England Journal of Medicine ahead of presentation Monday at the international conference of the American Thoracic Society, ATS 2022.

Additional results from the companion phase III DENALI study, also scheduled for presentation at ATS 2022 on Monday, showed treatment with the albuterol-budesonide investigational therapy to be associated with statistically significant improvement in lung function measured by forced expiratory volume in 1 second (FEV₁), compared to individual, non-fixed-dose use of albuterol and budesonide or placebo.

In a press statement, MANDALA and DENALI researcher Bradley Chipps, MD, medical director of the Capital Allergy & Respiratory Disease Center in Sacramento, California, noted that the trial data "strengthen the growing body of evidence around the value of as-needed anti-inflammatory treatment in asthma and support PTO27’s potential to transform the current rescue treatment approach."

Writing in NEJM, MANDALA lead researcher Alberto Papi, MD, of Ferrara Medical School, Ferrara, Italy, and colleagues, noted that while short-acting β₂-agonists (SABAs) have traditionally been recommended as rescue treatment for uncontrolled asthma, the therapy has little impact on underlying airway inflammation, "and over-reliance on SABAs serves as a metric for poor asthma control, with an associated risk of severe asthma exacerbation."

They further noted that, given the limitations of SABA alone as a rescue strategy, most treatment guidelines now call for inhaled glucocorticoid-containing rescue medication as the preferred rescue treatment.

Papi and colleagues wrote that the albuterol-budesonide combination therapy’s acceptable safety profile and greater efficacy compared to albuterol alone, "as well as the absence of a need to change underlying maintenance therapy, indicate that this fixed-dose combination could replace SABA alone as rescue therapy in patients with moderate-to-severe asthma."

In MANDALA, a total of 3,132 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 μg of albuterol and 160 μg of budesonide self-delivered in two puffs, a fixed-dose combination of 180 μg of albuterol and 80 μg of budesonide, or 180 μg of albuterol. Patients were instructed on the proper technique for using the metered-dose inhaler, and they were told to use the trial medication as needed in response to symptoms.

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 endpoint was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population.

"At baseline, the mean ACQ-5 score was 2.6 across the three trial groups, indicating poorly controlled asthma," the study authors wrote. "During the trial, patients reported that the mean (±SD) percentage of days they had taken their maintenance medication was 74.7±25.6% (median, 84.6%). Adherence was similar in the three trial groups."

"The intention-to-treat analysis showed that the risk of a severe asthma exacerbation, in a time to-event analysis, 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], 0.62-0.89; P=0.001)," the researchers wrote, with the hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, being 0.84 (95% CI, 0.71-1.00; P=0.052).

Among the other main findings, the study authors wrote:

• "In pre-planned efficacy analysis that included data collected during the on-treatment period before treatment discontinuation or a change in maintenance therapy, the hazard ratio for severe asthma exacerbation in the higher dose combination group, as compared with the albuterol-alone group, was 0.73 (95% CI, 0.61-0.88) and… 0.83 (95% CI, 0.70-0.99) in the lower-dose combination group…
• "The annualized rate of severe asthma exacerbations was 0.43 (95% CI, 0.33-0.58) in the higher-dose combination group and 0.58 (95% CI, 0.44 to 0.77) in the albuterol-alone group (rate ratio, 0.75; 95% CI, 0.61-0.91). The annualized rate of severe asthma exacerbations was 0.48 (95% CI, 0.37-0.63) in the lower-dose combination group and 0.60 (95% CI, 0.46-0.79) in the albuterol-alone group (rate ratio, 0.81; 95% CI, 0.66-0.98)…
• "At week 24, a response on the ACQ-5 (i.e. a decrease of at least 0.5 points from the baseline score) was observed in 66.8% of the patients in the higher-dose combination group and in 62.1% of those in the albuterol-alone group, for an odds ratio of 1.22 (95% CI, 1.02 to 1.47)." The corresponding ACQ-5 response in the lower-dose combo group was 64.7% compared to 61.6% in the albuterol-alone group (OR, 1,13; 95% CI, 0.95-1.35).
• Adverse events were similar in the three trial groups—46.2%, 47.1%, and 46.4% in the higher dose combo, lower dose combo and albuterol alone groups, respectively. The corresponding rate of serious adverse events was 5.2%, 3.8%, and 4.5%, respectively.

Nasopharyngitis, headache, and upper respiratory tract infections were the most common adverse events in the trial. Covid-19 occurred in 4.2% to 4.9% of patients in the three groups during the trial.

"The finding of a mean number of medication doses per day of less than 1.5 across the three trial groups shows that the patients used the albuterol-budesonide combination as they used albuterol alone," the researchers wrote, adding that, "unlike albuterol monotherapy, the fixed-dose combination allows patients to adjust the dose of inhaled glucocorticoid according to their own symptom-driven use of a bronchodilator in response to worsening asthma episodes."

Trial limitations include "the lack of measurements of the fraction of exhaled nitric oxide level, which would have allowed for a direct assessment of anti-inflammatory effects; the small number of children, which precludes conclusions being drawn in this important subpopulation; and the fact that growth indexes could not be assessed because of the small numbers and short period of observation of children in this trial," the study authors wrote.

This research was funded by the drug development company Avillion, which is developing PT027 for AstraZeneca. Papi reported receiving grants and serving as a paid consultant for AstraZeneca, and grants and/or consulting fees from Boehringer Ingelheim, Chiesi Farmaceutici, ELPEN Pharmaceuticals, GlaxoSmithKline, Merck, Novartis, Sanofi Pasteur Inc, Teva Pharmaceuticals and others. Chipps reported serving as a consultant for AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Regeneron, Sanofi US. Other researchers reported being employees of AstraZeneca or Avillon LLP.

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