For most of the 83 years since its pathological description, treatment of cystic fibrosis has focused on ameliorating its associated signs and symptoms. Following approval of the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator in 2012, 1 Ramsey BW Davies J McElvaney NG et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.

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treatment could target the basic defect in people with cystic fibrosis in whom CFTR protein dysfunction is amenable to such therapy. As the availability of therapies in this drug class has expanded to more and younger people with cystic fibrosis over the past decade, 2 Middleton PG Mall MA Drevinek P et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele.

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some questions remain. As these drugs might be needed throughout the lifespan of patients, do new safety issues arise with long-term use? Do these drugs show efficacy beyond the phase 3 trials? Can initiation early in life prevent or mitigate complications of cystic fibrosis? In patients with established complications, can we modify the course of the disease? To begin to answer these questions, studies published in The Lancet Respiratory Medicine by Jordana E Hoppe and colleagues, 3 Hoppe JE Chilvers M Ratjen F et al. Long-term safety of lumacaftor–ivacaftor in children aged 2–5 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a multicentre, phase 3, open-label, extension study. Lancet Respir Med. 2021; (published online May 6.) Mark A Chilvers and colleagues, 4 Chilvers MA Davies JC Milla C et al. Long-term safety and efficacy of lumacaftor–ivacaftor therapy in children aged 6–11 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a phase 3, open-label, extension study. Lancet Respir Med. 2021; (published online Jan 28.) and Patrick A Flume and colleagues 5 Flume PA Biner RF Downey DG 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; (published online Feb 10.) evaluated the safety and efficacy of combination CFTR modulator therapy (either lumacaftor–ivacaftor or tezacaftor–ivacaftor) administered for up to 120 weeks in children aged 2–5 years and 6–11 years, and in older children (aged ≥12 years) and adults.