In the phase 3 MANDALA trial, as-needed albuterol-budesonide pressurized metered-dose inhaler significantly reduced severe exacerbation risk vsas-needed albuterol in patients with moderate-to-severe asthma receiving inhaled corticosteroid-containing maintenance therapy. This study (DENALI) was conducted to address the US Food and Drug Administration combination rule, which requires a combination product to demonstrate that each component contributes to its efficacy. Do both albuterol and budesonide contribute to the efficacy of the albuterol-budesonide combination pressurized metered-dose inhaler in patients with asthma? This phase 3, double-blind trial randomized patients aged≥ 12 years with mild-to-moderate asthma 1:1:1:1:1 to four-times-daily albuterol-budesonide 180/160 μg or 180/80 μg, albuterol 180 μg, budesonide 160 μg, or placebo for 12weeks. Dual-primary efficacy end points included change from baseline in FEV1 area under the curve from 0 to 6h (FEV1 AUC0-6h) over 12weeks (assessing albuterol effect) and trough FEV1 at week 12 (assessing budesonide effect). Of 1,001 patients randomized, 989 were≥ 12 years old and evaluable for efficacy. Change from baseline in FEV1 AUC0-6h over 12weeks was greater with albuterol-budesonide 180/160 μg vsbudesonide 160 μg (least-squares mean [LSM] difference, 80.7 [95%CI, 28.4-132.9] mL; P= .003). Change in trough FEV1 at week 12 was greater with albuterol-budesonide 180/160 and 180/80 μg vsalbuterol 180 μg (LSM difference, 132.8 [95%CI, 63.6-201.9] mL and 120.8 [95%CI, 51.5-190.1] mL, respectively; both P< .001). Day 1 time to onset and duration of bronchodilation with albuterol-budesonide were similar to those with albuterol. The albuterol-budesonide adverse event profile was similar to that of the monocomponents. Both monocomponents contributed to albuterol-budesonide lung function efficacy. Albuterol-budesonide was well tolerated, even at regular, relatively high daily doses for 12weeks, with no new safety findings, supporting its use as a novel rescue therapy. ClinicalTrials.gov; No.: NCT03847896; URL: www. gov.