1. 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
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Patrick A Flume, Reta Fischer Biner, Damian G Downey, Cynthia Brown, Manu Jain, Rainald Fischer, Kris De Boeck, Gregory S Sawicki, Philip Chang, Hildegarde Paz-Diaz, Jaime L Rubin, Yoojung Yang, Xingdi Hu, David J Pasta, Stefanie J Millar, Daniel Campbell, Xin Wang, Neil Ahluwalia, Caroline A Owen, Claire E Wainwright, Ronald L. Gibson, Steven M. Rowe, Noah Lechtzin, Richard C. Ahrens, Karen S. McCoy, Moira Aitken, Scott H. Donaldson, Kimberly Ann McBennett, Joseph M. Pilewski, Joanne Billings, Carlos Milla, Ronald Rubenstein, Daniel Brian Rosenbluth, Rachel Linnemann, Michael R. Powers, Christopher Fortner, Carla Anne Frederick, Theodore G. Liou, Philip Black, Janice Wang, John L. Colombo, Maria Berdella, Maria Veronica Indihar, Cynthia D. Brown, Michael Anstead, Lara Bilodeau, Leonard Sicilian, James Jerome Tolle, Kathryn Moffett, Samya Nasr, Jennifer Taylor-Cousar, Tara Lynn Barto, Nicholas Antos, John S. Rogers, Bryon Quick, Henry R. Thompson, Gregory Sawicki, Bruce Barnett, Robert L. Zanni, Thomas C. Smith, Karen D. Schultz, Claire Keating, Patrick Flume, Gregory J. Omlor, Alix Ashare, Karen Voter, Nighat Mehdi, Maria Gabriela Tupayachi Ortiz, Tonia E. Gardner, Steven R. Boas, Barbara Messore, Edith Zemanick, Raksha Jain, Michael McCarthy, Dana G. Kissner, Kapilkumar Patel, John McNamara, Julie Philley, Ariel Berlinski, Francisco J. Calimano, Terry Chin, Douglas Conrad, Cori Daines, Hengameh H. Raissy, Thomas G. Keens, Jorge E. Lascano, Bennie McWilliams, Brian Morrissey, Santiago Reyes, Subramanyam Chittivelu, Sabiha Hussain, Arvey Stone, James Wallace, Ross Klingsberg, Julie A. Biller, Stephanie Bui, Olaf Sommerburg, Elisabetta Bignamini, Mirella Collura, Alexander Moller, Donatello Salvatore, Chantal Belleguic, Lea Bentur, Ori Efrati, Eitan Kerem, Dario Prais, Esther Quintana Gallego, Peter Barry, Galit Livnat-Levanon, Jose Ramon Villa Asensi, David Stuart Armstrong, Oscar Asensio de la Cruz, Francis Gilchrist, Diana Elizabeth Tullis, Bradley Quon, Larry C. Lands, Nancy Morrison, Annick Lavoie, Barry Linnane, Okan Elidemir, Felix Ringshausen, Matthias Kappler, Helge Hebestreit, Jochen Mainz, Alexander Kiefer, Cordula Koerner-Rettberg, Doris Staab, Wolfgang Gleiber, Tacjana Pressler, Florian Stehling, Andreas Hector, Sivagurunathan Sutharsan, Lutz Naehrlich, Damian Downey, Jane Carolyn Davies, Robert Ian Ketchell, Mary Patricia Carroll, Simon Doe, Gordon MacGregor, Edward Fairbairn Nash, Nicholas Withers, Daniel Gavin Peckham, Martin James Ledson, Sonal Kansra, Timothy William Rayner Lee, Bertrand Delaisi, Gilles Rault, Jean Le Bihan, Dominique Hubert, Isabelle Fajac, Isabelle Sermet-Gaudelus, Marleen Bakker, Bert Arets, Christiane De Boeck, Raphael Chiron, Philippe Reix, Catherine Mainguy, Eva van Braeckel, Anne Malfroot, Isabelle Durieu, Nadine Desmazes Dufeu, Anne Prevotat, Renske van der Meer, Petrus Merkus, E.J.M. Weersink, Isabel Barrio Gomez-Aguero, Silvia Gartner, Amparo Sole Jover, Antonio Alvarez Fernandez, Desmond William Cox, Edward F. McKone, Barry James Plant, Hiranjan Selvadurai, Simon David Bowler, Claire Elizabeth Wainwright, Daniel Smith, Peter Gordon Middleton, John William Wilson, Sonia Volpi, Carla Colombo, Benedetta Fabrizzi, Vincenzina Lucidi, Federico Cresta, Salvatore Cucchiara, Ernst Eber, Helmut Ellemunter, Isidor Huttegger, Lena Hjelte, Christina Krantz, Marita Gilljam, and Pulmonology
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Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Indoles ,Cystic Fibrosis ,Cystic Fibrosis Transmembrane Conductance Regulator ,Quinolones ,Aminophenols ,Cystic fibrosis ,Time ,Ivacaftor ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Benzodioxoles ,030212 general & internal medicine ,Israel ,biology ,business.industry ,Australia ,medicine.disease ,Cystic fibrosis transmembrane conductance regulator ,Discontinuation ,Europe ,Drug Combinations ,Treatment Outcome ,Clinical research ,030228 respiratory system ,Tolerability ,Mutation ,North America ,biology.protein ,Female ,business ,medicine.drug - Abstract
Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.
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- 2021