Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials

作者：Ahmet Uluer, Gordon MacGregor, Pilar Azevedo, V. Indihar, Claire L. Keating, Marcus Alexander Mall, Edward F. McKone, Bonnie W. Ramsey, Steven Mark Rowe, Ronald C. Rubenstein, Jennifer L. Taylor‐Cousar, Elizabeth D. Tullis, Lael M. Yonker, Chenghao Chu, Anna P. Lam, Nitin Nair, Patrick R. Sosnay, Simon Tian, Fredrick Van Goor, Lakshmi Viswanathan, David Waltz, Linda T. Wang, Yingmei Xi, Joanne L. Billings, Alex Robert Horsley, Alex Robert Horsley, Edward Fairbairn Nash, Marleen Bakker, Renske van der Meer, Petrus Merkus, Christof J. Majoor, Karen McCoy, Joanne L. Billings, Krishna Pancham, James Tolle, Bryon Quick, Ahmet Uluer, Emily DiMango, Adupa Rao, Santiago Reyes, Ross C. Klingsberg, Celeste Barreto, Victor E. Ortega, Donna Beth Willey‐Courand, C. Schwarz, Sivagurunathan Sutharsan, Rainald Fischer, Jane Carolyn Davies, Jamie M Duckers, Alex Robert Horsley, Simon J Doe, Edward Fairbairn Nash, Marleen Bakker, Harry G.M. Heijerman, Renske van der Meer, Petrus Merkus, Christof J. Majoor, George Marty Solomon, Christian A. Merlo, Jennifer Griffonnet, Joseph M. Pilewski, Jordan Dunitz, Saba Sheikh, Ronald C. Rubenstein, Daniel Rosenbluth, Theodore G. Liou, M.V. Indihar, Krishna Pancham, Lael M. Yonker, Samya Z. Nasr, Jennifer Griffonnet, Cynthia D. Brown, Gregory S. Sawicki, Jennifer R. Ruddy, Emily DiMango, Bryan A. Garcia, Andrew T. Braun, Alex H. Gifford, Nighat Mehdi, Maria Tupayachi Ortiz, Raksha Jain, Francisco J. Calimano, Jimmy Johannes, Cori L. Daines, Jason J. Fullmer, Joel D. Mermis, Christopher Barrios, Ngoc P. Ly, Brian P. Casserly, Stephan Eisenmann, Helge U. Hebestreit, Alexander Kiefer, Sivagurunathan Sutharsan, Rainald Fischer, Gordon MacGregor, Daniel Gavin Peckham, Martin James Ledson, Eva Van Braeckel, Petrus Merkus, Noel Gerard McElvaney, Edward F. McKone, Barry J. Plant, Lucy D. Burr, Daniel J. Smith, Peter Gordon Middleton, John W. Wilson · 发表于：The Lancet Respiratory Medicine · 年份：2023 · DOI：10.1016/s2213-2600(22)00504-5 · 被引用次数：74 · 研究领域：Cystic Fibrosis Research Advances、Pediatric health and respiratory diseases、Chemical and Physical Studies

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing. METHODS: from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete. FINDINGS: of 15·9 percentage points (11·3 to 20·6) and -0·1 percentage points (-6·4 to 6·1), respectively, in sweat chloride concentration of -45·5 mmol/L (-49·7 to -41·3) and -2·6 mmol/L (-8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and -5·0 points (-16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor-tezacaftor-deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity. INTERPRETATION: Once-daily dosing with vanzacaftor-tezacaftor-deutivacaftor was safe and wel...