Original Article|Articles in Press

Long-term tezacaftor/ivacaftor safety and efficacy in people with cystic fibrosis and an F508del-CFTR mutation: 96-week, open-label extension of the EXTEND trial

Published:December 27, 2022DOI:


      • In Study 661-110 of TEZ/IVA in pwCF and the F508del-CFTR mutation:
        • pwCF aged ≥12 years completed 96 additional weeks of treatment, totaling 216 weeks
        • Improvements in ppFEV1 and PEx were maintained for the additional 96 weeks
        • TEZ/IVA was generally safe and well tolerated
      • TEZ/IVA safety profile was sustained throughout the additional treatment period.



      Study 661-110 (EXTEND) is a phase 3, open-label, three-part rollover study designed to assess the long-term safety and efficacy of tezacaftor/ivacaftor (TEZ/IVA) in participants aged ≥12 years homozygous for F508del (F/F) or heterozygous for F508del and a residual function mutation (F/RF). TEZ/IVA was shown to be safe and efficacious for up to 120 weeks in Part A. Here we report results from Part B, which evaluated safety and efficacy for an additional 96 weeks.


      Part B enrolled participants aged ≥12 years with CF and F/F or F/RF genotypes who completed TEZ/IVA treatment in either Study 661-110 Part A, Study 661-112 (F/F), or Study 661-114 (F/F). Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination once daily (morning) and IVA 150 mg once daily (evening) for 96 weeks. Safety endpoints included adverse events (AEs) and serum liver function tests. Efficacy endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and pulmonary exacerbation (PEx) rate.


      464 participants were enrolled from Part A (n=377) and other eligible studies (n=87); 463 received ≥1 dose of TEZ/IVA. Overall, 92.2% had ≥1 AE, 0.9% had AEs leading to treatment discontinuation, and 29.4% reported serious AEs. The most common AEs, which were generally consistent with common manifestations of CF, included infective PEx of CF, cough, nasopharyngitis, hemoptysis, and headache. Lung function was maintained over 96 weeks in both genotype groups. PEx rates per year were comparable with Part A.


      TEZ/IVA was generally safe and well tolerated over a further 96 weeks; safety data were consistent with Part A. Improvements in ppFEV1 and PEx rates were maintained for an additional 96 weeks in Part B.



      AE (adverse event), ALT (alanine aminotransferase), AST (aspartate transaminase), BMI (body mass index), CF (cystic fibrosis), CFTR (cystic fibrosis transmembrane conductance regulator), F/F (homozygous for the F508del-CFTR mutation), F/RF (heterozygous for the F508del-CFTR mutation and a residual function CFTR mutation), IVA (ivacaftor), PEx (pulmonary exacerbations), ppFEV1 (percent predicted forced expiratory volume in 1 second), SD (standard deviation), TEZ (tezacaftor), ULN (upper limit of normal)
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        • Bell SC
        • Mall MA
        • Gutierrez H
        • Macek M
        • Madge S
        • Davies JC
        • Burgel PR
        • Tullis E
        • Castaños C
        • et al.
        The future of cystic fibrosis care: a global perspective.
        Lancet Respir Med. 2020; 8: 65-124
        • De Boeck K
        • Amaral MD.
        Progress in therapies for cystic fibrosis.
        Lancet Respir Med. 2016; 4: 662-674
        • Boyle MP
        • De Boeck K.
        A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect.
        Lancet Respir Med. 2013; 1: 158-163
        • Salvatore D
        • Padoan R
        • Buzzetti R
        • Amato A
        • Giordani B
        • Ferrari G
        • Majo F.
        Patients with cystic fibrosis having a residual function mutation: data from the Italian registry.
        Pediatr Pulmonol. 2019; 54: 150-157
        • Castellani C
        • Cuppens H
        • Macek Jr., M
        • Cassiman JJ
        • Kerem E
        • Durie P
        • Tullis E
        • Assael BM
        • Bombieri C
        • et al.
        Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.
        J Cyst Fibros. 2008; 7: 179-196
        • Taylor-Cousar JL
        • Munck A
        • McKone EF
        • van der Ent CK
        • Moeller A
        • Simard C
        • Wang LT
        • Ingenito EP
        • McKee C
        • et al.
        Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del.
        N Engl J Med. 2017; 377: 2013-2023
        • Rowe SM
        • Daines C
        • Ringshausen FC
        • Kerem E
        • Wilson J
        • Tullis E
        • Nair N
        • Simard C
        • Han L
        • et al.
        Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis.
        N Engl J Med. 2017; 377: 2024-2035
        • Flume PA
        • Biner RF
        • Downey DG
        • Brown C
        • Jain M
        • Fischer R
        • De Boeck K
        • Sawicki GS
        • Chang P
        • et al.
        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.
        Lancet Respir Med. 2021; 9: 733-746
        • Wainwright CE
        • Elborn JS
        • Ramsey BW
        • Marigowda G
        • Huang X
        • Cipolli M
        • Colombo C
        • Davies JC
        • De Boeck K
        • et al.
        Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.
        N Engl J Med. 2015; 373: 220-231
        • Konstan MW
        • McKone EF
        • Moss RB
        • Marigowda G
        • Tian S
        • Waltz D
        • Huang X
        • Lubarsky B
        • Rubin J
        • et al.
        Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study.
        Lancet Respir Med. 2017; 5: 107-118
        • McKone EF
        • Borowitz D
        • Drevinek P
        • Griese M
        • Konstan MW
        • Wainwright C
        • Ratjen F
        • Sermet-Gaudelus I
        • Plant B
        • et al.
        Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST).
        Lancet Respir Med. 2014; 2: 902-910
        • Donaldson SH
        • Pilewski JM
        • Griese M
        • Cooke J
        • Viswanathan L
        • Tullis E
        • Davies JC
        • Lekstrom-Himes JA
        • Wang LT.
        Tezacaftor/ivacaftor in subjects with cystic fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR.
        Am J Respir Crit Care Med. 2018; 197: 214-224
      1. FDA approves new breakthrough therapy for cystic fibrosis.
        U.S. Food & Drug Administration, 2019 (Available at) (Accessed November 21, 2022)
        • Ridley K
        • Condren M.
        Elexacaftor-tezacaftor-ivacaftor: the first triple-combination cystic fibrosis transmembrane conductance regulator modulating therapy.
        J Pediatr Pharmacol Ther. 2020; 25: 192-197
        • Heijerman HGM
        • McKone EF
        • Downey DG
        • Van Braeckel E
        • Rowe SM
        • Tullis E
        • Mall MA
        • Welter JJ
        • Ramsey BW
        • et al.
        Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial.
        Lancet. 2019; 394: 1940-1948