P094 A Phase II study to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of BI 1291583 in patients with cystic fibrosis bronchiectasis (the Clairafly™ study)

Objectives: Bronchiectasis, a key pathology in CF, is characterised by abnormal, scarred and irreversibly dilated bronchi. Neutrophilic airway inflammation is a central feature of bronchiectasis, leading to high levels of neutrophil-derived serine proteases, including neutrophil elastase (NE), proteinase-3 (PR3) and cathepsin G (CatG) in the sputum of patients with CF bronchiectasis (CFBE). Serine proteases are key drivers of tissue destruction and lung disease progression in CF, activated by cathepsin C (CatC) during neutrophil maturation in the bone marrow. BI 1291583 is a potent and highly selective inhibitor of CatC. Clairafly™ aims to assess safety, PK and PD of BI 1291583 in CFBE patients. Methods: Clairafly™ is a multicentre, randomised, placebo-controlled, double-blind, parallel-group, Phase 2 clinical trial. Participants must be ≥18 years old with a clinical diagnosis of CF, bronchiectasis confirmed by CT scan and a history of pulmonary exacerbations requiring antibiotic treatment in the 12 months prior to Visit 1 (≥2 exacerbations or ≥1 exacerbation + SGRQ Symptoms score >40). Patients with moderate/severe liver disease, absolute blood neutrophil count <1000/mm3 or eGFR <30mL/min at Visit 1 will be excluded. After a 6-week screening period, patients will be randomised (2:1) to receive BI 1291583 (QD) or placebo (QD) for 12 weeks with a 4-week follow-up. The primary endpoint is the occurrence of treatment-emergent adverse events up to Week 16. Secondary endpoints include PD (relative change from baseline in sputum NE activity at Week 8) and PK (AUC and Cmax). The trial design is under review by the European Clinical Trial Network and the Cystic Fibrosis Foundation Therapeutic Development Network; amendments will be included in the Clinical Trial Protocol. Results: Clairafly™ is estimated to begin August 2023. Conclusion: Clairafly™ will assess the safety, PK and PD of BI 1291583, an inhibitor of CatC, in CFBE to inform the design of Phase 3 trials.