Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis.
Steven M Rowe, Cori Daines, Felix C Ringshausen, Eitan Kerem, John Wilson, Elizabeth Tullis, Nitin Nair, Christopher Simard, Linda Han, Edward P Ingenito, Charlotte McKee, Julie Lekstrom-Himes, Jane C Davies
Author Information
Steven M Rowe: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
Cori Daines: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
Felix C Ringshausen: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
Eitan Kerem: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
John Wilson: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
Elizabeth Tullis: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
Nitin Nair: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
Christopher Simard: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
Linda Han: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
Edward P Ingenito: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
Charlotte McKee: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
Julie Lekstrom-Himes: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
Jane C Davies: From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.M.R.); the Arizona Respiratory Center, University of Arizona, Tucson (C.D.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research, Hannover, Germany (F.C.R.); Hadassah Hebrew University Medical Center, Jerusalem, Israel (E.K.); Alfred Health, Melbourne, VIC, Australia (J.W.); St. Michael's Hospital, Toronto (E.T.); Vertex Pharmaceuticals, Boston (N.N., C.S., L.H., E.P.I., C.M., J.L.-H.); and Imperial College and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.).
BACKGROUND: Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had Cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function. patients were randomly assigned to one of six sequences, each involving two 8-week intervention periods separated by an 8-week washout period. They received tezacaftor-ivacaftor, ivacaftor monotherapy, or placebo. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV) from the baseline value to the average of the week 4 and week 8 measurements in each intervention period. RESULTS: The number of analyzed intervention periods was 162 for tezacaftor-ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV was 6.8 percentage points for tezacaftor-ivacaftor and 4.7 percentage points for ivacaftor alone (P<0.001 for both comparisons). Scores on the respiratory domain of the Cystic fibrosis Questionnaire-Revised, a quality-of-life measure, also significantly favored the active-treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor-ivacaftor and few for ivacaftor alone (1% of patients) and placebo (<1%). CONCLUSIONS: CFTR modulator therapy with tezacaftor-ivacaftor or ivacaftor alone was efficacious in patients with Cystic fibrosis who were heterozygous for the Phe508del deletion and a CFTR residual-function mutation. (Funded by Vertex Pharmaceuticals and others; EXPAND ClinicalTrials.gov number, NCT02392234 .).
Associated Data
ClinicalTrials.gov | NCT02392234; NCT02392234
References
Proc Am Thorac Soc. 2007 Aug 1;4(4):378-86
[PMID: 17652505]
