Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study

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Abstract

Background: Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods: Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov (NCT02565914). Findings: Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation: Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding: Vertex Pharmaceuticals Incorporated.

Original languageEnglish
Pages (from-to)733-746
Number of pages14
JournalThe Lancet Respiratory Medicine
Volume9
Issue number7
DOIs
StatePublished - Jul 2021

Bibliographical note

Funding Information:
We thank the patients and their families for participating in this trial and the trial investigators and coordinators for their contributions to the trial. Editorial coordination and support were provided by Thomas Pickette, Vertex Pharmaceuticals; Thomas Pickette may own stock or stock options in that company. Medical writing, editorial support, and coordination were provided by the funder. Medical writing and editorial support were provided under the direction of the authors by Christopher Edwards and Karen Kaluza Smith. Christopher Edwards and Karen Kaluza Smith are employees of ArticulateScience, which received funding from Vertex Pharmaceuticals. This study was supported by Vertex Pharmaceuticals.

Funding Information:
All authors received non-financial support (assistance with manuscript preparation) from ArticulateScience, which received funding from Vertex Pharmaceuticals. CAO, DC, HP-D, JLR, NA, PC, XH, and YY are employees of Vertex Pharmaceuticals and may own stock or stock options in Vertex Pharmaceuticals. CB declares grants from Vertex Pharmaceuticals during the conduct of the study; and grants from Cystic Fibrosis Foundation Therapeutics, Translate Bio, Concert Pharmaceuticals, Parlon Sciences, Nivalis Therapeutics, Anthera Pharmaceuticals, and PTC Therapeutics outside of the submitted work. CEW was on an advisory board for Vertex; is editor for Respirology (associate editor) and Thorax (deputy editor); has honoraria from BMJ, DKBmed, Gilead, In Vivo Academy, Novartis, Thorax, University of Miami, and Vertex; has received a research grant from Novo Nordisk; has been study investigator for Boehringer Ingelheim and Vertex; and declares travel expenses from Vertex. DGD reports grants and personal fees from Vertex Pharmaceuticals, Proteostasis, and Chiesi outside the submitted work. GSS reports personal fees from and advisory board for Vertex Pharmaceuticals during the conduct of the study; and grants from Vertex Pharmaceuticals and personal fees from Gilead Sciences outside the submitted work. DJP and SJM are employees of ICON Clinical Research, which was paid by Vertex Pharmaceuticals for providing analytical services on this project; ICON Clinical Research is paid by various pharmaceutical, biotechnology, and device companies for providing clinical research services outside the submitted work. KDB received consultancy from Boehringer, Protalix, Raptor, Novabiotics, Eloxx, and Chiesi outside the submitted work; speaker fees from Teva outside the submitted work; did consultancy or was a principal investigator in studies for Galapagos outside the submitted work; was a member of steering committee, advisory board or was principal investigator in studies for Vertex Pharmaceuticals outside the submitted work. MJ reports grants, personal fees, advisory board, and speaker's bureau from Vertex Pharmaceuticals outside the submitted work. PAF reports grants and personal fees from Vertex Pharmaceuticals outside the submitted work. RF reports grants for study conduct from Vertex Pharmaceuticals during the conduct of the study. XW was an employee of Vertex Pharmaceuticals at the time the study was conducted and may own stock or stock options in Vertex Pharmaceuticals. RFB declares no competing interests.

Publisher Copyright:
© 2021 Elsevier Ltd

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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