A Phase 2 randomised study to establish efficacy, safety and dosing of a novel oral cathepsin C inhibitor, BI 1291583, in adults with bronchiectasis: Airleaf.

New therapies are needed to prevent exacerbations, improve quality of life and slow disease progression in bronchiectasis. Inhibition of cathepsin C (CatC) activity has the potential to decrease activation of neutrophil-derived serine proteases in patients with bronchiectasis, thereby reducing airway inflammation, improving symptoms, reducing exacerbations and preventing further airway damage. Here we present the design of a phase 2 trial (Airleaf™; NCT05238675) assessing the efficacy and safety of a novel CatC inhibitor, BI 1291583, in adult patients with bronchiectasis. This multinational, randomised, double-blind, placebo-controlled, parallel-group, dose-finding study has a screening period of at least 6 weeks, a treatment period of 24-48 weeks and a follow-up period of 4 weeks. ∼240 adults with bronchiectasis of multiple aetiologies will be randomised to placebo once daily, or BI 1291583 1 mg once daily, 2.5 mg once daily or 5 mg once daily in a 2:1:1:2 ratio, stratified by Pseudomonas aeruginosa infection and maintenance use of macrolides. The primary efficacy objective is to evaluate the dose-response relationship for the three oral doses of BI 1291583 versus placebo on time to first pulmonary exacerbation up to Week 48 (the primary end-point). Efficacy will be assessed using exacerbations, patient-reported outcomes, measures of symptoms, sputum neutrophil elastase activity and pulmonary function testing. Safety assessment will include adverse event reporting, physical examination, monitoring of vital signs, safety laboratory parameters, 12-lead electrocardiogram, and periodontal and dermatological assessments. If efficacy and safety are demonstrated, results will support further investigation of BI 1291583 in phase 3 trials.
Competing Interests: Conflict of interest: J.D. Chalmers reports grants from GSK, Boehringer Ingelheim, Zambon, Insmed, Grifols, Novartis, Gilead and AstraZeneca, and is an associate editor of this journal. A. Gupta, A. Eleftheraki, C. Diefenbach and W. Sauter are employees of Boehringer Ingelheim International GmbH. S.H. Chotirmall reports grants paid to his institution from the Singapore Ministry of Health's National Medical Research Council under its Clinician-Scientist Individual Research Grant (MOH-000141), Clinical-Scientist Award (MOH-000710) and National Research Foundation Singapore under its COVID-19 Research Fund administered by the Singapore Ministry of Health's National Medical Research Council (MOH-000409), consulting fees from CSL Behring, Pneumagen Ltd and Boehringer Ingelheim, lecture fees from AstraZeneca, and participation in Data Safety and Monitoring Committees for Inovio Pharmaceuticals and Imam Abdulrahman Bin Faisal University. A. Armstrong reports consulting fees from AbbVie, Almirall, Arcutis, ASLAN, Beiersdorf, BMS, Dermavant, EPI, Incyte, Nimbus, Dermira, Eli Lilly, Janssen, Leo Pharma, Modernizing Medicine, Novartis, Ortho Dermatologics, Regeneron, Sanofi Genzyme, Sun Pharma, UCB Pharma, Boehringer Ingelheim, Parexel and Pfizer, payment or honoraria from AbbVie, ASLAN, Boehringer Ingelheim, BMS, EPI, Incyte, Leo, UCB, Janssen, Lilly, Novartis, Ortho Dermatologics, Sun, Dermavant, Dermira, Sanofi Regeneron, Parexel, Pfizer, Almirall, Arcutis, Nimbus and ModMed, participation on advisory boards for Boehringer Ingelheim and Parexel, and is on the board of directors for the American Academy of Dermatology. P. Eickholz reports payment or honoraria for lectures from Boehringer Ingelheim, Sanofi Aventis, Kulzer, CP GABA and Philips, and lectures primarily in the dental field. N. Hasegawa reports grants for a clinical trial and consulting fees from Insmed. P.J. McShane reports study funding to her institution from Boehringer Ingelheim and speaker fees from Insmed. A.E. O'Donnell reports grants for study funding from Insmed, AstraZeneca, Zambon and the US Bronchiectasis Research Registry, consulting fees from Insmed, Boehringer Ingelheim, Zambon, Electromed, AstraZeneca and Xellia, payment for CME from Vindico Medical Education, participation in a Data Safety Monitoring Board for Parexel, and a role with the US Bronchiectasis Research Registry. M. Shteinberg reports grants paid to her institution from GSK, Trumed and Novartis, consulting fees from GSK, Boehringer Ingelheim, Kamada, Zambon and Vertex, payment or honoraria from Boehringer Ingelheim, GSK, AstraZeneca, Teva, Novartis and Kamada, support for attending meetings from Novartis, Actelion, Boehringer Ingelheim, GSK and Rafa, participation on advisory boards from Bonus Therapeutics (Israel), unpaid fiduciary roles for EMBARC Management and the Israel Pulmonology Society Board, and receipt of supply to a clinical trial from Trudell. H. Watz has nothing to disclose.
(Copyright ©The authors 2023.)