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

James D Chalmers; Abhya Gupta; Sanjay H Chotirmall; April Armstrong; Peter Eickholz; Naoki Hasegawa; Pamela J McShane; Anne E O'Donnell; Michal Shteinberg; Henrik Watz; Anastasia Eleftheraki; Claudia Diefenbach; Wiebke Sauter

doi:10.1183/23120541.00633-2022

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

ERJ Open Res. 2023 Jun 26;9(3):00633-2022. doi: 10.1183/23120541.00633-2022. eCollection 2023 May.

Authors

Affiliations

¹ Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK.
² Boehringer Ingelheim International GmbH, Biberach, Germany.
³ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
⁴ Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore, Singapore.
⁵ University of Southern California, Los Angeles, CA, USA.
⁶ Department of Periodontology, Goethe University Frankfurt, Frankfurt, Germany.
⁷ Department of Infectious Diseases, Keio University, Tokyo, Japan.
⁸ University of Texas Health Science Center at Tyler, Tyler, TX, USA.
⁹ Georgetown University Medical Center, Washington, DC, USA.
¹⁰ Lady Davis Carmel Medical Center, Haifa, Israel.
¹¹ Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany.

Abstract

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.