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

• Published in: The European respiratory journal Vol. 59; no. 2; p. 2100746
• Main Authors: Goss, Christopher H., Fajac, Isabelle, Jain, Raksha, Seibold, Wolfgang, Gupta, Abhya, Hsu, Ming-Chi, Sutharsan, Sivagurunathan, Davies, Jane C., Mall, Marcus A.
• Format: Journal Article
• Language: English
• Published: England European Respiratory Society 01.02.2022
• Subjects: Adolescent; Adult; Cystic Fibrosis - drug therapy; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Double-Blind Method; Forced Expiratory Volume; Humans; Mucociliary Clearance; Original s; Respiratory Function Tests - methods
• ISSN: 0903-1936; 1399-3003; 1399-3003
• DOI: 10.1183/13993003.00746-2021

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. We present results from BALANCE-CF 1, a phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 placebo for 4 weeks on top of standard of care in adults and adolescents with CF. 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 ) 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 , 200 µg twice-daily dose 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 placebo. BI 1265162 up to 200 µg twice daily was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers. BI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated.