TY - JOUR
T1 - Efficacy and safety of inhaled ENaC inhibitor BI 1265162 in patients with cystic fibrosis
T2 - BALANCE-CF 1, a randomised, phase II study
AU - Goss, Christopher H.
AU - Fajac, Isabelle
AU - Jain, Raksha
AU - Seibold, Wolfgang
AU - Gupta, Abhya
AU - Hsu, Ming Chi
AU - Sutharsan, Sivagurunathan
AU - Davies, Jane C.
AU - Mall, Marcus A.
N1 - Funding Information:
Support statement: This work was supported by Boehringer Ingelheim. Funding information for this article has been deposited with the Crossref Funder Registry.
Funding Information:
Acknowledgements: The authors would like to thank the study participants, study investigators and coordinators, the Cystic Fibrosis Foundation (CFF), the European Cystic Fibrosis Society (ECFS), the CFF Therapeutics Development Network, the CFF-DMC Chair and members, the ECFS-Clinical Trials Network, the ECFS Lung Clearance Index Core Facility (Clare Saunders and Christopher Short for test set-up, performance and analysis) and the Cystic Fibrosis Community Advisory Board in Europe. The authors would also like to thank the clinical study leader Anne-Caroline Picard for her operational excellence and Tina Luo for assistance with statistical analysis. Medical writing assistance, in the form of the preparation and revision of the manuscript, was supported financially by Boehringer Ingelheim and provided by Lee Kempster at MediTech Media (London, UK), under the authors’ conceptual direction and based on feedback from the authors. The study was supported by the National Institute of Health Research (NIHR) through the Imperial Biomedical Research Centre, the NHLI/Royal Brompton Clinical Research Facility and a Senior Investigator award (to J.C. Davies).
Funding Information:
Conflict of interest: C.H. Goss reports grants from the Cystic Fibrosis Foundation, the European Commission and NIH (NHLBI, NIDDK and NCRR), during the conduct of the study; personal fees for grant review board work from Gilead Sciences, personal fees for data monitoring committee work from Novartis, grants from the NIH and FDA, non-financial support (reimbursement for travel and meeting attendance) and other (serving as trial lead with site contract) from Boehringer Ingelheim, personal fees for lectures from Vertex Pharmaceuticals, outside the submitted work. I. Fajac reports grants and personal fees for consultancy from Boehringer, during the conduct of the study; grants and personal fees for consultancy from Proteostasis Therapeutics and Vertex Pharmaceuticals, personal fees for consultancy from Kither Biotech, outside the submitted work. R. Jain reports grants and personal fees for consultancy from Vertex Pharmaceuticals, grants from the CF Foundation, Sound Pharma, Armata Pharmaceuticals, Corbus Pharmaceuticals and Genetech, grants and personal fees for advisory board work from Boehringer Ingelheim, outside the submitted work. W. Seibold is an employee of Boehringer Ingelheim. A. Gupta is an employee of Boehringer Ingelheim. M-C. Hsu is a former employee of Boehringer Ingelheim (China) and current employee of Shanghai Junshi Biosciences Co Ltd. S. Sutharsan reports personal fees for advisory board work from Vertex Pharmaceuticals, personal fees for lectures from Novartis, outside the submitted work. J.C. Davies reports other (advisory board and clinical trial lead) from Algipharma AS, Bayer AG, Galapagos NV and Proteostasis Therapeutics, Inc., other (advisory board) from Boehringer Ingelheim Pharma GmbH & Co. KG, Nivalis Therapeutics, Inc., Raptor Pharmaceuticals, Inc., Enterprise, Novartis, ProQR Therapeutics III BV, Pulmocide and Flatley, other (advisory board and trial design assistance) from ImevaX GmbH and ProQR Therapeutics III BV, other (advisory board and national co-ordinator/global co-investigator) from Vertex Pharmaceuticals (Europe) Limited, grants from the CF Trust, other (educational activities) from Teva, outside the submitted work. M.A. Mall reports grants, personal fees for advisory board work and non-financial support (travel expenses) from Boehringer Ingelheim, during the conduct of the study; personal fees for advisory board work, consultancy and lectures from Boehringer Ingelheim, personal fees for advisory board work and consultancy from Arrowhead Pharmaceuticals, Santhera, Enterprise Therapeutics, Antabio and Kither Biotech, grants and personal fees for advisory board work, consultancy and lectures from Vertex Pharmaceuticals, personal fees for consultancy from Galapagos and Sterna Biologicals, personal fees for lectures from Celtaxys, outside the submitted work.
Publisher Copyright:
© 2022 European Respiratory Society. All rights reserved.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - Background Inhibition of the epithelial sodium channel (ENaC) in cystic fibrosis (CF) airways provides a mutation-agnostic approach that could improve mucociliary clearance in all CF patients. BI 1265162 is an ENaC inhibitor with demonstrated pre-clinical efficacy and safety already demonstrated in humans. Objective We present results from BALANCE-CFTM 1, a phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 versus placebo for 4 weeks on top of standard of care in adults and adolescents with CF. Results Initially, 28 randomised subjects (BI 1265162 200 µg twice daily n=14, placebo twice daily n=14) were assessed at an interim futility analysis. Compared with placebo, numerical changes of –0.8% (95% CI –6.6 to 4.9%) in percentage predicted forced expiratory volume in 1s (ppFEV1) and +2.1 units (95% CI –2.4 to 6.5 units) in lung clearance index (LCI) were observed in the active group, meeting a pre-defined stopping rule; accordingly, the study was terminated. Recruitment had continued during the interim analysis and pending results; 24 patients were added across three dose levels and placebo. The final results including these patients (+1.5% ppFEV1, 200 µg twice-daily dose versus placebo) were not supportive of relevant clinical effect. Furthermore, LCI change was not supportive, although interpretation was limited due to insufficient traces meeting quality criteria. A 9.4-point improvement in the Cystic Fibrosis Questionnaire – Revised Respiratory Domain was observed in the 200 µg twice daily dose group versus placebo. BI 1265162 up to 200 µg twice daily was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers. Conclusion BI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated.
AB - Background Inhibition of the epithelial sodium channel (ENaC) in cystic fibrosis (CF) airways provides a mutation-agnostic approach that could improve mucociliary clearance in all CF patients. BI 1265162 is an ENaC inhibitor with demonstrated pre-clinical efficacy and safety already demonstrated in humans. Objective We present results from BALANCE-CFTM 1, a phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 versus placebo for 4 weeks on top of standard of care in adults and adolescents with CF. Results Initially, 28 randomised subjects (BI 1265162 200 µg twice daily n=14, placebo twice daily n=14) were assessed at an interim futility analysis. Compared with placebo, numerical changes of –0.8% (95% CI –6.6 to 4.9%) in percentage predicted forced expiratory volume in 1s (ppFEV1) and +2.1 units (95% CI –2.4 to 6.5 units) in lung clearance index (LCI) were observed in the active group, meeting a pre-defined stopping rule; accordingly, the study was terminated. Recruitment had continued during the interim analysis and pending results; 24 patients were added across three dose levels and placebo. The final results including these patients (+1.5% ppFEV1, 200 µg twice-daily dose versus placebo) were not supportive of relevant clinical effect. Furthermore, LCI change was not supportive, although interpretation was limited due to insufficient traces meeting quality criteria. A 9.4-point improvement in the Cystic Fibrosis Questionnaire – Revised Respiratory Domain was observed in the 200 µg twice daily dose group versus placebo. BI 1265162 up to 200 µg twice daily was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers. Conclusion BI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated.
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U2 - 10.1183/13993003.00746-2021
DO - 10.1183/13993003.00746-2021
M3 - Article
C2 - 34385272
AN - SCOPUS:85124850752
SN - 0903-1936
VL - 59
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 2
M1 - 2100746
ER -