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

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