The efficacy of AIRSUPRA was evaluated in MANDALA and DENALI as described below. While patients 12 to 17 years were included in these trials, AIRSUPRA is not approved in this age group; therefore, efficacy results are presented for adults only.

MANDALA   
The efficacy of AIRSUPRA 180 mcg/160 mcg was evaluated in patients 12 years of age and older with moderate to severe asthma in MANDALA (NCT03769090), a randomized, double-blind, multicenter study. MANDALA was a variable length exacerbation study with at least 24 weeks duration.

Patients 12 years of age and older were randomized (1:1:1) and received at least one dose of AIRSUPRA (AS-BD MDI 180 mcg/160 mcg), albuterol/budesonide (AS-BD MDI 180 mcg/80 mcg) or albuterol (AS MDI 180 mcg) as needed. Patients were required to be receiving medium to high dose ICS or low to high dose ICS/long-acting beta2-adrenergic agonists (LABA), with or without another controller medicine as maintenance therapy. All patients continued their own maintenance therapy throughout the trial. MANDALA was conducted in symptomatic patients with moderate to severe asthma, a history of at least 1 severe asthma exacerbation in the year prior to screening, pre-bronchodilator FEV1 40 to < 90% of predicted normal (for patients aged 12 to < 18 years old, ≥ 60%) and a confirmed reversibility to albuterol. 

The adult efficacy population (n=2940) in MANDALA had a mean age of 52 years (range: 18-84 years), with 66% female and 82% Caucasian, and 25% of Hispanic or Latino ethnicity. The median duration of asthma was 21 years (range 1 to 80 years) since the first diagnosis of asthma. The mean pre-bronchodilator percent predicted FEV1 was 63% (range 33% - 101%).

The overall patterns of use of AIRSUPRA and AS MDI 180 mcg were similar during the randomized treatment period.

The primary efficacy endpoint was the time to first severe asthma exacerbation (defined as worsening or onset of asthma symptoms that required systemic corticosteroids for at least 3 days or an emergency room visit that led to the use of systemic corticosteroids for at least 3 days or a hospitalization for at least 24 hours due to asthma).

Efficacy results are shown for only the approved adult population. Treatment with AIRSUPRA, compared with AS MDI 180 mcg, demonstrated statistically significant reductions in the risk of severe asthma exacerbations among adult patients, as assessed by the time to first severe asthma exacerbation as described in Figure 1. Compared with AS MDI 180 mcg, patients receiving AIRSUPRA experienced a statistically significant 28% reduction (Hazard Ratio [HR] 0.72; 95% CI: 0.60, 0.86) in the risk of a severe asthma exacerbation (p<0.001).

Figure 1. Kaplan-Meier Cumulative Incidence Curve for Time to First Exacerbation1

There were reductions in severe asthma exacerbation risk regardless of exacerbation history (1 or > 1 in the past year), baseline lung function, and asthma severity (defined by background maintenance therapy) compared with AS MDI 180 mcg.

Treatment with AIRSUPRA 180 mcg/160 mcg statistically significantly reduced the annual rate of severe asthma exacerbations by 24% compared with AS MDI 180 mcg as shown in Table 2.

The annualized total systemic corticosteroid (SCS) dose due to asthma was calculated for each patient during the study period. For patients treated with AIRSUPRA 180 mcg/160 mcg the annualized total SCS dose when compared with AS MDI 180 mcg was statistically significantly different, with a reduction in mean annualized dose of 40 mg per patient [AIRSUPRA (87 mg) vs AS MDI 180 (127 mg)]. 

Asthma control was assessed using the Asthma Control Questionnaire (ACQ-5) responder analysis. Responders were defined as those patients with an improvement of 0.5 or more in overall ACQ-5 score at Week 24 compared to baseline. The percentage of ACQ-5 adult responders at Week 24 for AIRSUPRA 180 mcg/160 mcg was 67% compared with 63% for AS MDI 180 mcg (odds ratio 1.21; 95% CI: 1.01, 1.46). 

Asthma quality of life was assessed using the Asthma Quality of Life Questionnaire in patients 12 years of age and older (AQLQ+12). Responders were defined as those with an improvement of 0.5 or more in AQLQ score at Week 24 compared to baseline. The percentage of adult responders at Week 24 for AIRSUPRA 180 mcg/160 mcg was 52% (odds ratio 1.22; 95% CI: 1.01, 1.47) compared with 47% for AS MDI 180 mcg.

DENALI   
The efficacy of AIRSUPRA on lung function was evaluated in patients 12 years of age and older with mild to moderate asthma who were previously treated with as-needed short-acting beta2-agonists (SABA) alone or with low-dose ICS maintenance therapy plus as-needed SABA. DENALI (NCT03847896) was a double-blind, active-comparator and placebo-controlled lung function study conducted over 12 weeks. Patients were randomized 1:1:1:1:1 to receive AIRSUPRA (AS-BD MDI 180 mcg/160 mcg), AS-BD MDI 180 mcg/80 mcg, BD MDI 160 mcg, AS MDI 180 mcg, or Placebo MDI, all administered 4 times daily. Only the results for the approved recommended dose of AIRSUPRA are described below.

The population 18 years of age and older (n=964) had a mean age of 50 years (range: 18-90 years) with 63% female and 89% Caucasian, and 28% of Hispanic or Latino ethnicity. 

Efficacy results are presented for only the approved adult population. The onset of bronchodilation (as defined by a ≥ 15% increase in FEV1 post-dose within 30 minutes on Day 1) was observed in 51% of patients treated with AIRSUPRA 180 mcg/160 mcg and 43% of patients treated with AS MDI 180 mcg. Following a single dose on Day 1, the median time to onset and mean duration of bronchodilation were 7.5 and 186.9 minutes with AIRSUPRA 180 mcg/160 mcg and 10.0 and 167.9 minutes with AS MDI 180 mcg, respectively.