A phase III study (AIRTIVITY®) to assess the efficacy, safety and tolerability of the DPP1 (CatC) inhibitor BI 1291583 in adults and adolescents with bronchiectasis of various etiologies

Abstract

Background: Bronchiectasis (BE) is a chronic lung disease characterized by neutrophilic inflammation and imbalances between neutrophil serine proteases (NSPs) and antiproteases. NSPs are activated by dipeptidyl peptidase 1 (DPP1, or cathepsin C); therefore, DPP1 inhibition is expected to improve the NSP–antiprotease imbalance in BE. The Phase II AIRLEAF®study, which showed that the DPP1 inhibitor BI 1291583 reduced pulmonary exacerbation (PEx) risk in adults with BE, supports this. BE is increasingly prevalent in both adults and children; however, it remains underdiagnosed and neglected in children. Given the extensive experience in adults, children with BE are expected to benefit from DPP1 inhibition because they also have high NSP levels. Here, we outline the design of the Phase III AIRTIVITY®study, which will assess the efficacy, safety and tolerability of BI 1291583 in adults and adolescents with BE of various etiologies, including CF—a common cause of BE. Methods: AIRTIVITY®is a randomized, double-blind study that will assess the safety and efficacy of BI 1291583 in ∼1680 adults (240 adults with CF) and 75 adolescents (up to 30% with CF; 12–< 18 years old; bodyweight of ≥35 kg) with computed tomography-confirmed BE of various etiologies. Participants will receive BI 1291583 2.5 mg or placebo (2:1) for 52–76 weeks (Figure 1). Simulations from a population pharmacokinetic model based on Phase I and AIRLEAF®data predict that adolescent participants will have similar BI 1291583 exposure to adults. Both adults and adolescents must have a history of PExs requiring antibiotic treatment in the year prior to screening. Results: The primary objective of AIRTIVITY®is to show superiority of BI 1291583 2.5 mg compared with placebo based on the primary endpoint: the annualized rate of PExs up toWeek 76. AtWeek 52, the main secondary endpoints include change from baseline in lung function and Quality of Life-Bronchiectasis respiratory symptom domain score. Up toWeek 76, the main secondary endpoints include time to first PEx and annualized rate of severe PExs. Using pediatric BE guidelines [1], adolescent-specific PEx endpoints will also be assessed. Additional adolescent-specific secondary endpoints include change in Lung Clearance Index over time. The safety of BI 1291583 will be monitored through clinical assessment, adverse event reporting, monitoring of growth, and safety laboratory parameters. Conclusions: Based on the promising Phase II AIRLEAF®results, AIRTIVITY®will assess the efficacy of BI 1291583 2.5 mg. The adolescentspecific endpoints examined in this study may support future development of BI 1291583 in younger people with BE. AIRTIVITY®is due to begin in Q2 2025, with the first adolescent planned to be screened in Q4 2025. Acknowledgements: This study was supported and funded by Boehringer Ingelheim International GmbH. The authors meet ICMJE criteria, received writing support and did not receive payment related to the development of the abstract.