Tezacaftor/ivacaftor in people with cystic fibrosis who stopped lumacaftor/ivacaftor due to respiratory adverse events.

Background: Increased 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 (ppFEV ₁ ) 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.
Methods: Participants ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV ₁ of ≥25% and ≤90% were randomized 1:1 and treated with tezacaftor/ivacaftor or placebo for 56 days.
Results: Of 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) ppFEV ₁ 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 ppFEV ₁ from baseline to the average value of days 28 and 56 was 2.7 percentage points with tezacaftor/ivacaftor vs placebo.
Conclusions: Tezacaftor/ivacaftor was generally safe, well tolerated, and efficacious in people ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV ₁ of ≥25% and ≤90% who previously discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.
Competing Interests: Declaration of Competing Interests All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex. Additional disclosures are as follows. BGB, MED, and NA are employees of Vertex and may own stock or stock options in Vertex. PKA, TJF and XY are former employees of Vertex and may own stock or stock options in Vertex. CS received a grant from Vertex and personal fees from Vertex, PTI, Chiesi, and Teva outside the submitted work. RF received an honorarium from Vertex during the conduct of the study. SMR received grants, personal fees, and nonfinancial support from Vertex during the conduct of the study; grants from Bayer, Forest Research Institute, AstraZeneca, Nivalis, Novartis, Galapagos/AbbVie, Proteostasis, Eloxx, Celtaxsys, PTC, and Vertex; personal fees from Bayer, Celtaxsys, Novartis, and Vertex; and nonfinancial support from Vertex outside the submitted work. SS received personal fees from Proteostasis, Novartis and Vertex outside the submitted work; has served as an investigator in clinical trials for Galapagos, Proteostasis, Celtaxsys, Flatley, Novartis, and Vertex; and has consulted for Proteostasis and Vertex. RCK and RE have no additional disclosures.
(Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)