Tezacaftor/ivacaftor in people with cystic fibrosis who stopped lumacaftor/ivacaftor due to respiratory adverse events |
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| Authors: | Carsten Schwarz Sivagurunathan Sutharsan Ralph Epaud Ross C Klingsberg Rainald Fischer Steven M Rowe Paul K Audhya Neil Ahluwalia Xiaojun You Thomas J Ferro Margaret E Duncan Bote G Bruinsma |
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| Institution: | 1. Christiane Herzog Zentrum Berlin/Charité–Universitätsmedizin Berlin, Berlin, Germany;2. Division of Cystic Fibrosis, Department of Pulmonary Medicine, Faculty of Medicine, Universitat Duisburg Essen–Ruhrlandklinik, Essen, Germany;3. Cystic Fibrosis and Rare Lung Disease Centre, Centre Hospitalier Intercommunal de Créteil, Créteil, France;4. Tulane University School of Medicine, New Orleans, LA, USA;5. Pneumologische Praxis München-Pasing, Munich, Germany;6. The University of Alabama at Birmingham, Birmingham, AL, USA;7. Formerly of Vertex Pharmaceuticals Incorporated, Boston, MA, USA;8. Vertex Pharmaceuticals Incorporated, Boston, MA, USA |
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| Abstract: | BackgroundIncreased rates of respiratory adverse events have been observed in people ≥12 years of age with cystic fibrosis homozygous for the Phe508del-CFTR mutation treated with lumacaftor/ivacaftor, particularly in those with percent predicted forced expiratory volume in 1 s (ppFEV1) of <40%. We evaluated the safety, tolerability, and efficacy of tezacaftor/ivacaftor in people with cystic fibrosis homozygous for Phe508del-CFTR who discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.MethodsParticipants ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV1 of ≥25% and ≤90% were randomized 1:1 and treated with tezacaftor/ivacaftor or placebo for 56 days.ResultsOf 97 participants, 94 (96.9%) completed the study. The primary endpoint was incidence of predefined respiratory adverse events of special interest (chest discomfort, dyspnea, respiration abnormal, asthma, bronchial hyperreactivity, bronchospasm, and wheezing): tezacaftor/ivacaftor, 14.0%; placebo, 21.3%. The adverse events were mild or moderate in severity. None were serious or led to treatment interruption or discontinuation. Overall, the discontinuation rate was similar between groups. The mean (SD) ppFEV1 at baseline was 44.6% (16.1%) with tezacaftor/ivacaftor and 48.0% (18.1%) with placebo. The posterior mean difference in absolute change in ppFEV1 from baseline to the average value of days 28 and 56 was 2.7 percentage points with tezacaftor/ivacaftor vs placebo.ConclusionsTezacaftor/ivacaftor was generally safe, well tolerated, and efficacious in people ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV1 of ≥25% and ≤90% who previously discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms. |
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