A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis

被引：73
作者：
Habib, Al-Rahim R. [1 ]
Kajbafzadeh, Majid [1 ]
Desai, Sameer [2 ]
Yang, Connie L. [3 ]
Skolnik, Kate [4 ]
Quon, Bradley S. [5 ]
机构：
[1] Univ Sydney, Sch Med, Sydney, NSW, Australia
[2] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada
[3] Univ British Columbia, Dept Pediat, Div Resp Med, Vancouver, BC, Canada
[4] Univ Calgary, Dept Med, Div Respirol, Calgary, AB, Canada
[5] Univ British Columbia, Dept Med, St Pauls Hosp, Ctr Heart Lung Innovat, Vancouver, BC, Canada
来源：
SCIENTIFIC REPORTS | 2019年 / 9卷 / 1期
关键词：
PHE508DEL CFTR; LUMACAFTOR/IVACAFTOR COMBINATION; TEZACAFTOR-IVACAFTOR; DOUBLE-BLIND; IN-VITRO; MUTATION; F508DEL-CFTR; THERAPY; PHASE-3; POTENTIATOR;
D O I：
10.1038/s41598-019-43652-2
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Several placebo-controlled trials have been recently published evaluating novel therapies targeting the defective CFTR protein. This systematic review examines the clinical efficacy and safety of CFTR modulators in individuals with cystic fibrosis (CF) with specific genetic mutations. Online sources were searched for placebo-controlled, parallel-design clinical trials investigating CFTR modulators from January 1, 2005 to March 31, 2018. The primary outcome of interest was FEV1% predicted (ppFEV(1)). Fourteen RCTs met our eligibility criteria. The largest improvement in ppFEV(1) favouring treatment was observed for ivacaftor (IVA) in G551D individuals (>= 6 years old). Both tezacaftor-ivacaftor (TEZ-IVA) and lumacaftor-ivacaftor (LUM-IVA) also improved ppFEV(1) in F508del homozygous individuals but there was increased reporting of respiratory adverse events with LUM-IVA compared to placebo. IVA also significantly improved ppFEV(1) in a sub-group of individuals >= 18 years old with an R117H mutation. No significant improvements in ppFEV(1) were observed for IVA, LUM, or TEZ in F508del homozygous individuals, LUM or LUM-IVA in F508del heterozygous individuals, or ataluren in individuals with a nonsense mutation. Significant improvements in ppFEV(1) and other clinical outcomes were observed for IVA in G551D individuals, TEV-IVA and LUM-IVA in F508del homozygous individuals, and IVA in adults with a R117H mutation.
引用
收藏
页数：9
相关论文
共 42 条
  • [1] Effect of VX-770 in Persons with Cystic Fibrosis and the G551D-CFTR Mutation
    Accurso, Frank J.
    Rowe, Steven M.
    Clancy, J. P.
    Boyle, Michael P.
    Dunitz, Jordan M.
    Durie, Peter R.
    Sagel, Scott D.
    Hornick, Douglas B.
    Konstan, Michael W.
    Donaldson, Scott H.
    Moss, Richard B.
    Pilewski, Joseph M.
    Rubenstein, Ronald C.
    Uluer, Ahmet Z.
    Aitken, Moira L.
    Freedman, Steven D.
    Rose, Lynn M.
    Mayer-Hamblett, Nicole
    Dong, Qunming
    Zha, Jiuhong
    Stone, Anne J.
    Olson, Eric R.
    Ordonez, Claudia L.
    Campbell, Preston W.
    Ashlock, Melissa A.
    Ramsey, Bonnie W.
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (21) : 1991 - 2003
  • [2] A faux 3′-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay
    Amrani, N
    Ganesan, R
    Kervestin, S
    Mangus, DA
    Ghosh, S
    Jacobson, A
    [J]. NATURE, 2004, 432 (7013) : 112 - 118
  • [3] [Anonymous], 2017, COCHRANE DATABASE SY
  • [4] [Anonymous], LANCET RESP MED
  • [5] [Anonymous], COCHRANE DATABASE SY
  • [6] Gene therapy in cystic fibrosis
    Armstrong, David K.
    Cunningham, Steve
    Davies, Jane C.
    Alton, Eric W. F. W.
    [J]. ARCHIVES OF DISEASE IN CHILDHOOD, 2014, 99 (05) : 465 - 468
  • [7] PURIFICATION AND FUNCTIONAL RECONSTITUTION OF THE CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR)
    BEAR, CE
    LI, CH
    KARTNER, N
    BRIDGES, RJ
    JENSEN, TJ
    RAMJEESINGH, M
    RIORDAN, JR
    [J]. CELL, 1992, 68 (04) : 809 - 818
  • [8] A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial
    Boyle, Michael P.
    Bell, Scott C.
    Konstan, Michael W.
    McColley, Susanna A.
    Rowe, Steven M.
    Rietschel, Ernst
    Huang, Xiaohong
    Waltz, David
    Patel, Naimish R.
    Rodman, David
    [J]. LANCET RESPIRATORY MEDICINE, 2014, 2 (07) : 527 - 538
  • [9] Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation
    Clancy, J. P.
    Rowe, Steven M.
    Accurso, Frank J.
    Aitken, Moira L.
    Amin, Raouf S.
    Ashlock, Melissa A.
    Ballmann, Manfred
    Boyle, Michael P.
    Bronsveld, Inez
    Campbell, Preston W.
    De Boeck, Kris
    Donaldson, Scott H.
    Dorkin, Henry L.
    Dunitz, Jordan M.
    Durie, Peter R.
    Jain, Manu
    Leonard, Anissa
    Mccoy, Karen S.
    Moss, Richard B.
    Pilewski, Joseph M.
    Rosenbluth, Daniel B.
    Rubenstein, Ronald C.
    Schechter, Michael S.
    Botfield, Martyn
    Ordonez, Claudia L.
    Spencer-Green, George T.
    Vernillet, Laurent
    Wisseh, Steve
    Yen, Karl
    Konstan, Michael W.
    [J]. THORAX, 2012, 67 (01) : 12 - 18
  • [10] Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study
    Davies, Jane C.
    Cunningham, Steve
    Harris, William T.
    Lapey, Allen
    Regelmann, Warren E.
    Sawicki, Gregory S.
    Southern, Kevin W.
    Robertson, Sarah
    Green, Yulia
    Cooke, Jon
    Rosenfeld, Margaret
    [J]. LANCET RESPIRATORY MEDICINE, 2016, 4 (02) : 107 - 115
12345