• Peter J Barry, Marcus A Mall, Antonio Álvarez, Carla Colombo, Karin M de Winter-de Groot, Isabelle Fajac, Kimberly A McBennett, Edward F McKone, Bonnie W Ramsey, Sivagurunathan Sutharsan, Jennifer L Taylor-Cousar, Elizabeth Tullis, Neil Ahluwalia, Lucy S Jun, Samuel M Moskowitz, Valentin Prieto-Centurion, Simon Tian, David Waltz, Fengjuan Xuan, Yaohua Zhang, Steven M Rowe, Deepika Polineni, and VX18-445-104 Study Group.
• From Manchester University NHS Foundation Trust, Manchester, United Kingdom (P.J.B.); Charité-Universitätsmedizin Berlin, the Berlin Institute of Health, and the German Center for Lung Research, Berlin (M.A.M.), and the Division of Cystic Fibrosis, Department of Pulmonary Medicine, University Medicine Essen-Ruhrlandklinik, University of Duisburg-Essen, Essen (S.S.) - all in Germany; Vall d'Hebron Barcelona Hospital Campus, Barcelona (A.A.); Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and the University of Milan - both in Milan (C.C.); Wilhelmina Children's Hospital-University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (K.M.W.-G.); Assistance Publique-Hôpitaux de Paris (AP-HP) Centre-Université de Paris Hôpital Cochin AP-HP, Paris (I.F.); Rainbow Babies and Children's Hospital, Cleveland (K.A.M.); St. Vincent's University Hospital, Dublin (E.F.M.); Seattle Children's Hospital, Seattle (B.W.R.); National Jewish Health, Denver (J.L.T.-C.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.A., L.S.J., S.M.M., V.P.-C., S.T., D.W., F.X., Y.Z.); the University of Alabama at Birmingham, Birmingham (S.M.R.); and the University of Kansas Medical Center, Kansas City (D.P.).
• N. Engl. J. Med. 2021 Aug 26; 385 (9): 815-825.

BackgroundElexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear.MethodsWe conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group.ResultsAfter the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group.ConclusionsElexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del-gating or Phe508del-residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).Copyright © 2021 Massachusetts Medical Society.

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