SAN FRANCISCO — Phase III results look very good for a two-drug combination inhaler in helping asthma patients regain symptom control when maintenance medications weren’t doing the job.
In the MANDALA trial, patients using the investigational product PT027, which combines 90 μg of albuterol with 80 μg of budesonide, were significantly less likely to experience severe exacerbations than those using albuterol alone by 26% (P=0.001), reported Alberto Papi, MD, of the University of Ferrara in Italy, and colleagues.
A version with a lower steroid dose (40 μg) also appeared to reduce severe exacerbation risk, but the 16% advantage over conventional albuterol-only treatment just missed statistical significance (P=0.052), they stated in the New England Journal of Medicine. Results are scheduled for presentation at the American Thoracic Society (ATS) annual meeting.
The idea behind the approach is that short-acting beta agonist (SABA) drugs, such as albuterol, are quite effective in reducing acute symptoms, but they do nothing about the underlying inflammation responsible for those symptoms, according to Papi and colleagues. The product’s developers, Avillion and AstraZeneca, reasoned that adding a steroid should do more to prevent symptoms from recurring.
For the study, 3,132 patients were randomized 1:1:1 to the three regimens: two actuations each of the 90/80 μg or 90/40 μg versions, or two actuations of 90 μg albuterol. In each case, patients were instructed to use the device when they experienced acute symptoms. They remained on whatever maintenance treatment they were using when enrolling, which consisted of long-acting beta agonists and inhaled corticosteroids, either individually or in combination and in a variety of doses.
To be eligible, patients needed to have experienced at least one exacerbation in the previous year (roughly 20% had had two or more) despite regular maintenance treatment. Patients, ages 4 years and older (about 3% of all participants) were enrolled; those younger than age 12 were excluded from the high-dose arm. Mean age was 49, about two-thirds were female, and the majority were white. Follow-up lasted 2 years.
The primary endpoint was severe exacerbation, defined as any of the following:
- Inpatient admission for asthma symptoms
- Emergency department or urgent care visit
- At least 3 days of systemic steroid therapy for worsening symptoms
Papi and colleagues also tracked a variety of secondary outcomes, such as time to first exacerbation, and safety parameters.
Annualized rates of severe exacerbation were 0.43 for the high-dose product versus 0.58 for albuterol alone, for a rate ratio of 0.75 (95% CI 0.61-0.91). Because the low-dose group included all the children, it was compared to a slightly different set of albuterol-only controls, such that annualized exacerbation rates in that comparison were 0.48 and 0.60, respectively. That rate ratio of 0.81 did achieve significance (95% CI 0.66-0.98).
Another secondary outcome was use of systemic steroids. This, too, favored the combination inhaler, with averages of 83.6 mg (prednisone equivalent) for the high-dose version, 94.7 mg with the lower dose, and 130.0/127.6 mg for the respective albuterol-only control groups.
Results in a different analysis comprising only those patients remaining on therapy without changing their maintenance regimens were essentially similar.
With respect to safety, there were no marked differences in rates of adverse events (AEs); 46%-47% of patients in each arm had some kind of AE. Nasopharyngitis was seen in 7.5% of the high-dose group versus 5.8% with the low-dose combo and 5.1% with albuterol alone.
The separate phase III DENALI trial included spirometric outcomes. In September 2021 press release, Avillion said the product showed superiority to albuterol alone in that study, though it provided no specifics. DENALI findings are also slated for presentation at ATS.
Neither Avillion nor AstraZeneca have indicated whether or when they plan to seek marketing approval for PT027.
The study was funded by Avillion with support from AstraZeneca. Some co-authors are Avillion or AstraZeneca employees.
Papi and co-authors disclosed multiple relationships with industry including Avillion and AstraZeneca.