Efficacy and safety of inhaled ENaC inhibitor BI 1265162 in patients with cystic fibrosis: BALANCE-CF 1, a randomised, phase II study.

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-CF ^TM 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 (ppFEV ₁ ) 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% ppFEV ₁ , 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.
Competing Interests: 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. Conflict of interest: 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. Conflict of interest: 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. Conflict of interest: W. Seibold is an employee of Boehringer Ingelheim. Conflict of interest: A. Gupta is an employee of Boehringer Ingelheim. Conflict of interest: M-C. Hsu is a former employee of Boehringer Ingelheim (China) and current employee of Shanghai Junshi Biosciences Co Ltd. Conflict of interest: S. Sutharsan reports personal fees for advisory board work from Vertex Pharmaceuticals, personal fees for lectures from Novartis, outside the submitted work. Conflict of interest: 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. Conflict of interest: 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.
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