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Ataluren/ivacaftor combination therapy: Two N‐of‐1 trials in cystic fibrosis patients with nonsense mutations
Author(s) -
Peabody Lever Jacelyn E.,
Mutyam Venkateshwar,
Hathorne Heather Y.,
Peng Ning,
Sharma Jyoti,
Edwards Lloyd J.,
Rowe Steven M.
Publication year - 2020
Publication title -
pediatric pulmonology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.866
H-Index - 106
eISSN - 1099-0496
pISSN - 8755-6863
DOI - 10.1002/ppul.24764
Subject(s) - ivacaftor , medicine , cystic fibrosis , cystic fibrosis transmembrane conductance regulator , nonsense , nonsense mutation , mutation , missense mutation , genetics , biology , gene
Premature termination codons (PTCs) in cystic fibrosis transmembrane conductance regulator (CFTR) produce nonfunctional protein. No approved therapies exist for PTC mutations, including W1282X. We hypothesized that ivacaftor, combined with readthrough therapy, may benefit W1282X patients. Two N‐of‐1 clinical trials were conducted with ataluren and ivacaftor in various combinations. No meaningful clinical benefit was observed in either patient with ivacaftor alone or ataluren/ivacaftor combination. However, isolated improvements of uncertain significance were noted by a nasal potential difference (NPD) and FEV 1 % with ivacaftor in Patient‐1 and with ataluren/ivacaftor combination by NPD and body mass index in Patient‐2. Drug regimen composed of readthrough agents and potentiators warrant further development for W1282X and other CFTR nonsense mutations.