Triple Therapy for Cystic Fibrosis <i>Phe508del</i> –Gating and –Residual Function Genotypes
Peter J. Barry, Marcus Mall, Antonio Álvarez, Carla Colombo, Karin M. de Winter‐de Groot, Isabelle Fajac, Kimberly McBennett, Edward F. McKone, Bonnie W. Ramsey, Sivagurunathan Sutharsan, Jennifer L. Taylor‐Cousar, Elizabeth Tullis, Neil Ahluwalia, Lucy S. Jun, Samuel M. Moskowitz, Valentin Prieto-Centurion, Simon Tian, David Waltz, Fengjuan Xuan, Yao‐Hua Zhang, Steven M. Rowe, Deepika Polineni
Abstract
BACKGROUND: allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear. METHODS: ) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group. RESULTS: that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group. CONCLUSIONS: -residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).