TY - JOUR
T1 - Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation
T2 - a double-blind, randomised, phase 3 trial
AU - Heijerman, Harry G M
AU - McKone, Edward F
AU - Downey, Damian G
AU - Van Braeckel, Eva
AU - Rowe, Steven M
AU - Tullis, Elizabeth
AU - Mall, Marcus A
AU - Welter, John J
AU - Ramsey, Bonnie W
AU - McKee, Charlotte M
AU - Marigowda, Gautham
AU - Moskowitz, Samuel M
AU - Waltz, David
AU - Sosnay, Patrick R
AU - Simard, Christopher
AU - Ahluwalia, Neil
AU - Xuan, Fengjuan
AU - Zhang, Yaohua
AU - Taylor-Cousar, Jennifer L
AU - McCoy, Karen S
N1 - Funding Information:
We thank the participants and their families for participating and the study investigators and coordinators for their contributions to the study. We thank the Cystic Fibrosis Foundation Therapeutics Development Network and the European Cystic Fibrosis Clinical Trials Network for their support of the study sites. The study was supported by Vertex Pharmaceuticals. The National Institutes of Health provided grant support to the University of Alabama at Birmingham (P30DK072482, R35HL135816, and U54TR001368) and Seattle Children's Hospital (P30-DK-089507, 5UL1 TR 0002319, and 1U01TR 002487). Editorial coordination and support were provided by Sarah Garber and Swati Thorat. SG is a former employee of Vertex Pharmaceuticals, and ST is an employee of Vertex Pharmaceuticals and may own stock or stock options in the company. Editorial assistance was provided by Katherine Mills-Lujan of ArticulateScience under the guidance of the authors and was supported by Vertex Pharmaceuticals.
Funding Information:
HGMH reports speaker fees from Chiesi, Horizon Pharma, PTC Therapeutics, TEVA, and Vertex; and fees for advisory board participation from Vertex and PTC Therapeutics. EFM reports grants from Gilead and Vertex, for which his institution (St Vincent's University Hospital, Dublin, Ireland) received payment; consulting fees from Vertex and Proteostasis; and non-financial support from Novartis. DGD reports grants from Chiesi, Gilead, Proteostasis and Vertex, for which his institution (Queen's University Belfast, Belfast, UK) received payment; speaker fees from Gilead and Vertex; and honoraria from Gilead and Proteostasis. EVB reports research grants from Vertex, Galapagos, and Zambon, for which her institution (Ghent University Hospital, Ghent, Belgium) received payment; and fees for advisory board participation for Vertex. SMR reports research grants from AstraZeneca, Bayer, Celtaxys, Eloxx, Forest Research Institute, Galapagos/AbbVie, N30/Nivalis, Novartis, PTC Therapeutics, Synedgen/Synspira, and Vertex, for which his institution (University of Alabama at Birmingham, Birmingham, AL, USA) received payment; consulting fees from Bayer, Celtaxys, Novartis, Renovion, Synedgen/Synspira, and Vertex; and fees for advisory board participation for Vertex. ET reports grants from AbbVie, Proteostasis, and Vertex, for which her institution (St Michael's Hospital, London, UK) received payment; and personal fees from Proteostasis and Vertex. MAM reports research grants from Vertex, for which his institution (Charité-Universitätsmedizin Berlin, Germany) received payment; consulting fees from Bayer, Galapagos, and Sterna Biologicals; fees for consulting and advisory board participation from Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Polyphor, ProQR Therapeutics, Sathera, Spyryx Bioscience, and Vertex; and speaker fees from Bayer, Boehringer Ingelheim, Celtaxys, and Vertex. JJW reports grants from Concert, Proteostasis, and Vertex, for which his institution (New York Medical College, New York, NY, USA) received payment. CMM, GM, SMM, DW, PRS, CS, NA, FX, and YZ are employees of Vertex and may own stock or stock options in that company. JLT-C reports research grants from Celtaxys, Bayer, Gilead, National Institutes of Health, Proteostasis, the Cystic Fibrosis Foundation, and Vertex, for which her institution (National Jewish Health, Denver, CO, USA) received payment; consulting fees from Celtaxys, Proteostasis, Santhera, and Vertex; fees for advisory board participation from Gilead, Protalix, and Vertex; speaker fees from Celtaxys, Proteostasis, and Vertex; and service on the Cystic Fibrosis Foundation Therapeutics Development Network Clinical Research Executive Committee and is Chair-Elect of the American Thoracic Society Clinical Problems Assembly Programming Committee. KSM reports research grants from Alcresta, Corbus, Novoteris, Proteostasis, Savara, Translate Bio, and Vertex, for which her institution (Nationwide Children's Hospital, Columbus, OH, USA) received payment. BWR declares no competing interests.
Funding Information:
We thank the participants and their families for participating and the study investigators and coordinators for their contributions to the study. We thank the Cystic Fibrosis Foundation Therapeutics Development Network and the European Cystic Fibrosis Clinical Trials Network for their support of the study sites. The study was supported by Vertex Pharmaceuticals. The National Institutes of Health provided grant support to the University of Alabama at Birmingham ( P30DK072482 , R35HL135816 , and U54TR001368 ) and Seattle Children's Hospital (P30-DK-089507, 5UL1 TR 0002319, and 1U01TR 002487). Editorial coordination and support were provided by Sarah Garber and Swati Thorat. SG is a former employee of Vertex Pharmaceuticals, and ST is an employee of Vertex Pharmaceuticals and may own stock or stock options in the company. Editorial assistance was provided by Katherine Mills-Lujan of ArticulateScience under the guidance of the authors and was supported by Vertex Pharmaceuticals.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/11/23
Y1 - 2019/11/23
N2 - Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. Methods: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV
1) of 40–90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV
1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. Findings: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV
1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference −45·1 mmol/L [95% CI −50·1 to −40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor. Interpretation: Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. Funding: Vertex Pharmaceuticals.
AB - Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. Methods: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV
1) of 40–90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV
1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. Findings: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV
1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference −45·1 mmol/L [95% CI −50·1 to −40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor. Interpretation: Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. Funding: Vertex Pharmaceuticals.
KW - Adolescent
KW - Aminophenols/administration & dosage
KW - Benzodioxoles/administration & dosage
KW - Child
KW - Chloride Channel Agonists/administration & dosage
KW - Cystic Fibrosis Transmembrane Conductance Regulator/genetics
KW - Cystic Fibrosis/drug therapy
KW - Double-Blind Method
KW - Drug Therapy, Combination
KW - Female
KW - Humans
KW - Indoles/administration & dosage
KW - Male
KW - Pyrazoles/administration & dosage
KW - Pyridines/administration & dosage
KW - Pyrrolidines/administration & dosage
KW - Quinolones/administration & dosage
KW - Sweat/chemistry
UR - http://www.scopus.com/inward/record.url?scp=85074786708&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(19)32597-8
DO - 10.1016/S0140-6736(19)32597-8
M3 - Article
C2 - 31679946
SN - 0140-6736
VL - 394
SP - 1940
EP - 1948
JO - The Lancet
JF - The Lancet
IS - 10212
ER -