Burnette, A.F.

Abstract Introduction Inhaled corticosteroid/fast-acting beta2-agonist combinations are recommended over albuterol-alone as rescue in asthma due to superior exacerbation reduction. In adults with asthma, BATURA and MANDALA demonstrated as-needed albuterol-budesonide 180/160 μg reduced the risk of severe exacerbation by 46% in mild and 28% in moderate-to-severe asthma for patients aged ≥18 years versus albuterol 180 μg. However, albuterol is the long-held rescue therapy standard for treatment of bronchoconstriction. In the ALbuterol-budesonide Treatment in Acute Airway Obstruction (ALTA) (NCT05555290) study, repetitive albuterol-budesonide 180/160 ug versus albuterol 180 ug treatment resulted in equally rapid improvement in lung function over 60 minutes and provided enhanced bronchodilation at 480 minutes post-mannitol challenge: least squares mean/LSM(standard error/SE) [95%CI] difference in ΔFEV1=91.2 (27.4) [36.7-145.7] mL. This post-hoc analysis of ALTA evaluated whether baseline lung function affects treatment response. Methods ALTA was a Phase 3b, multicenter, randomized, double-blind, 2-period, crossover study evaluating efficacy of repetitive albuterol-budesonide 180/160 μg vs albuterol 180 μg in adults with mild asthma experiencing ≥15% fall in FEV1 with cumulative mannitol exposure ≤635 mg. Inclusion criteria included use of short-acting beta2-agonist as the only pre-enrollment therapy for ≥4 weeks and pre-challenge FEV1 ≥1.500 L and 60%-<90% of predicted. Participants received albuterol-budesonide or albuterol at end-mannitol challenge (time 0) and 20, 40, and 60 minutes thereafter. FEV1 was assessed starting pre-mannitol challenge (-30 minutes) and over 480 minutes post-challenge. For participants with baseline FEV1 60%-<80% and 80%-<90% predicted, LSM(SE) [95%CI] difference between treatment arms in ΔFEV1 from time 0 min at 480 minutes was analyzed using a linear mixed effects model. Results 88 randomized participants receiving ≥1 dose of study drug were included: mean(SD) age=44.5(13.7) years; 56.8% female; mean(SD) FEV1=2.462(0.540) L (76.7[7.7]% predicted). 56 participants had baseline FEV1 ≥60%-<80% predicted; 32 had baseline FEV1 80%-<90% predicted. Percent fall in FEV1 post-challenge was similar between lung function subgroups. Improvement in FEV1 post-mannitol (time 0 min) at 480 min was greater with albuterol-budesonide vs albuterol treatment for both FEV1 subgroups: LSM(SE) [95%CI] difference 71.0(29.8) [11.0-131.0] mL, p = 0.021 in the lower and 114.0(55.1) [1.0-227.0] mL, p = 0.048 in the higher baseline FEV1 participants (Figure). There was no significant difference in the treatment by subgroup interaction, suggesting consistent treatment efficacy between subgroups. Conclusions Albuterol-budesonide relieves acute obstruction better than albuterol over time in mild asthma whether or not baseline lung function falls within a normal range. This abstract is funded by: AstraZeneca

Abstract RATIONALE: Albuterol-budesonide 180/160 µg is indicated in the US for as-needed treatment or prevention of bronchoconstriction and to reduce risk of exacerbations in patients ≥18 years old with asthma. The objective of the ALbuterol-budesonide Treatment in Acute airway obstruction (ALTA) study (NCT05555290) is to assess comparative efficacy, safety, and mechanisms of action of albuterol-budesonide 180/160 µg versus albuterol 180 µg in treating and preventing bronchoconstriction. This report describes the clinical profiles of patients meeting criteria for randomization into the trial. METHODS: ALTA is a phase 3b, multicenter, randomized, double-blind, 2-period, cross-over study evaluating the effects of repetitive dosing of albuterol-budesonide 180/160 µg versus albuterol 180 µg for treating adults treated as intermittent asthma and experiencing acute airway obstruction induced by repeated mannitol challenges. Inclusion criteria evaluated during screening include asthma diagnosis ≥6 months, prescribed and utilizing albuterol as the only asthma treatment for ≥4 weeks, pre-bronchodilator FEV1 ≥1.50 L and FEV1 ≥60% to <90% predicted, and positive response to a mannitol challenge (decrease in FEV1≥15% at ≤635 mg cumulative mannitol dose). Exclusion criteria include clinically significant lung disease other than asthma; any smoking in the prior 6 months or ≥10 pack-year smoking history; or a clinical encounter for asthma worsening within the past 4 weeks. RESULTS: Thus far, 84 patients have met the criteria for randomization into ALTA. Mean(SD) age=44.9(13.7) years, 56.0% female, 40.5% African American, 9.5% Hispanic/Latino. Clinical characteristics include 10.7% with 1 prior-year severe exacerbation; mean(SD) fractional exhaled nitric oxide=37.0(37.4) ppb; mean(SD) baseline pre-bronchodilator FEV1=2.464(0.538) L; mean(SD) baseline percent predicted FEV1=76.7(7.9)%; mean(SD) % fall in FEV1 with mannitol challenge=22.1(7.3)% at a mean(SD) cumulative mannitol dose of 146.4(176.3) mg. Despite being treated for intermittent asthma, based upon symptoms, lung function, and exacerbation history, no patients met NAEPP 2007 criteria for intermittent disease, and 13.1% fell into the mild, 78.6% moderate, and 8.3% severe persistent asthma categories (Figure). With respect to asthma control, as measured by Asthma Impairment and Risk Questionnaire scores, 60.7% had well-controlled, 20.2% not well-controlled, and 19.1% very poorly controlled disease. CONCLUSION: The baseline characteristics of patients in the ALTA study reveal that patients treated as intermittent asthma exhibit heterogeneity in clinical characteristics, airway hyper-reactivity, T2 inflammation, and disease severity and control. Additional genomic and biomarker data are forthcoming and altogether will provide an opportunity to address the mechanism of albuterol and budesonide interactions in a broad spectrum of asthma phenotypes.