Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial

Heijerman, H.G.M.; McKone, Edward F.; Downey, D.G.; Braeckel, Eva Van; Rowe, Steven M.; Tullis, Elizabeth; Mall, Marcus; Welter, John; Ramsey, Bonnie W.; McKee, Charlotte M.; Marigowda, Gautham; Moskowitz, Samuel M.; Waltz, David A.; Sosnay, Patrick R.; Simard, C; Ahluwalia, Neil; Xuan, Fengjuan; Zhang, Yaohua; Taylor‐Cousar, Jennifer L.; McCoy, Karen

doi:10.1016/s0140-6736(19)32597-8

Cited by 869 publications

(801 citation statements)

References 24 publications

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“…In both TEZ/IVA studies, lung function was measured before and 2 and 4 h after the first dose, and on day 15 an acute drop in lung function was not observed in either study [21,22]. Adverse events with ELX/TEZ/IVA that were more common in active groups than placebo were not increased in people with severe disease [23,24]. Hence, the cause of lung function decline and respiratory symptoms associated with LUM/IVA are more likely due to a unique effect not shared by TEZ/IVA.…”

Section: Adverse Events Resulting From Cftr Modulator Therapy In Peopmentioning

confidence: 99%

“…The addition of a second corrector, ELX, to TEZ/IVA resulted in improved CFTR function in excess of the TEZ/IVA effect. In clinical trials of treating people with CF with one or two F508del alleles, the ELX/TEZ/IVA combination led to a markedly improved lung function gain of 10-14% [23,24], with a reduction of exacerbations by 63% [23]. People with FEV 1 % pred <40% gained lung function (FEV 1 % pred) by of a mean 15.2% (95% CI 7.3-23.1%) (absolute) over placebo [23].…”

Section: Efficacy Of Cftr Modulators In People With Advanced Pulmonarmentioning

confidence: 99%

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Impact of CFTR modulator use on outcomes in people with severe cystic fibrosis lung disease

Shteinberg

Taylor‐Cousar

2020

Eur Respir Rev

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Drug compounds that augment the production and activity of the cystic fibrosis (CF) transmembrane regulator (CFTR) have revolutionised CF care. Many adults and some children with CF suffer advanced and severe lung disease or await lung transplantation. While the hope is that these drug compounds will prevent lung damage when started early in life, there is an ongoing need to care for people with advanced lung disease. The focus of this review is the accumulating data from clinical trials and case series regarding the benefits of CFTR modulator therapy in people with advanced pulmonary disease. We address the impact of treatment with ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor on lung function, pulmonary exacerbations, nutrition and quality of life. Adverse events of the different CFTR modulators, as well as the potential for drug–drug interactions, are discussed.

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Section: Adverse Events Resulting From Cftr Modulator Therapy In Peopmentioning

confidence: 99%

Section: Efficacy Of Cftr Modulators In People With Advanced Pulmonarmentioning

confidence: 99%

Impact of CFTR modulator use on outcomes in people with severe cystic fibrosis lung disease

Shteinberg

Taylor‐Cousar

2020

Eur Respir Rev

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“…After F508del homozygous patients received four weeks of treatment with the triple combination rather than tezacaftor plus ivacaftor, FEV 1 increased by 10.0% predicted and the Questionnaire scores improved by 17.4 points. Sweat chloride decreased by 45.1 mmol/L . These improvements are very impressive.…”

Section: From Treating Symptoms To Treating the Underlying Defectmentioning

confidence: 86%

Cystic fibrosis in the year 2020: A disease with a new face

2020

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“…Even though patients affected by CF have found therapies in molecules that help correct mutant-CFTR malfunctions (Heijerman et al, 2019;Middleton et al, 2019), and new such molecules are being discovered (Pedemonte et al, 2020), almost 10% of CF patients are still left with no such treatment. The potential use of KCa3.1 inhibitors correspond to what has been called a "mutationagnostic" treatment for CF, but also seems suitable for easing other muco-obstructive diseases affecting humans.…”

Section: Discussionmentioning

confidence: 99%

Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease

Vega

Guequén

Philp

et al. 2020

Preprint

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Airway mucociliary clearance (MCC) is the main mechanism of lung defense keeping the airways free of infection and mucus obstruction. Airways surface liquid (ASL) volume, ciliary beating and mucus are central for proper MCC, and are critically regulated by sodium (Na + ) absorption and anion secretion. Impaired MCC is a key feature of muco-obstructive disease. The calcium-activated potassium (K + )channel KCa.3.1, encoded by the Kcnn4 gene, participates in intestinal ion secretion and previous studies showed that its activation increase Na + absorption in airway epithelia, suggesting that hyperpolarization induced by KCa3.1 was sufficient to drive Na + absorption.However, its role in airway epithelial function is not fully understood. We therefore aimed to elucidate the role of KCa3.1 in MCC in a genetically engineered mouse model. We show that KCa3.1 inhibition reduced Na + absorption in mouse and human airway epithelium. Furthermore, the genetic deletion of Kcnn4 enhanced cilia beating frequency (CBF) and MCC ex vivo and in vivo.Kcnn4 was silenced in the Scnn1b-transgenic mouse (Scnn1b tg/+ ), a model of muco-obstructive lung disease triggered by increased epithelial Na + -absorption, leading to improvements in MCC and reduction of Na + -absorption. KCa3.1 deletion did not change the amount of mucus but did reduce mucus adhesion, neutrophil infiltration and emphysema. Our data support that KCa3.1 inhibition attenuated muco-obstructive disease in the Scnn1b tg/+ mice. K + -channel modulation may be a novel therapeutic strategy to treat muco-obstuctive lung diseases.

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Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial

Abstract: VX17-445-103 Trial Group (2019). Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet.

Cited by 869 publications

References 24 publications

Impact of CFTR modulator use on outcomes in people with severe cystic fibrosis lung disease

Impact of CFTR modulator use on outcomes in people with severe cystic fibrosis lung disease

Cystic fibrosis in the year 2020: A disease with a new face

Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease

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