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

VX17-445-103 Trial Group

doi:10.1016/S0140-6736(19)32597-8

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

VX17-445-103 Trial Group

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

137 Scopus citations

Abstract

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 (ppFEV₁) 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 ppFEV₁ 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 ppFEV₁ (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.

Original language	English (US)
Pages (from-to)	1940-1948
Number of pages	9
Journal	The Lancet
Volume	394
Issue number	10212
DOIs	https://doi.org/10.1016/S0140-6736(19)32597-8
State	Published - Nov 23 2019

ASJC Scopus subject areas

Medicine(all)

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10.1016/S0140-6736(19)32597-8

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@article{9226f2f0c875468092e6a462174ef987,

title = "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 = "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 (ppFEV1) 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 ppFEV1 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 ppFEV1 (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.",

author = "{VX17-445-103 Trial Group} and Heijerman, {Harry G.M.} and McKone, {Edward F.} and Downey, {Damian G.} and {Van Braeckel}, Eva and Rowe, {Steven M.} and Elizabeth Tullis and Mall, {Marcus A.} and Welter, {John J.} and Ramsey, {Bonnie W.} and McKee, {Charlotte M.} and Gautham Marigowda and Moskowitz, {Samuel M.} and David Waltz and Sosnay, {Patrick R.} and Christopher Simard and Neil Ahluwalia and Fengjuan Xuan and Yaohua Zhang and Taylor-Cousar, {Jennifer L.} and McCoy, {Karen S.} and Karen McCoy and Scott Donaldson and Seth Walker and James Chmiel and Ronald Rubenstein and Froh, {Deborah K.} and Isabel Neuringer and Manu Jain and Kathryn Moffett and Taylor-Cousar, {Jennifer L.} and Bruce Barnett and Gary Mueller and Patrick Flume and Floyd Livingston and Nighat Mehdi and Charlotte Teneback and John Welter and Raksha Jain and Dana Kissner and Kapilkumar Patel and Calimano, {Francisco J.} and Jimmy Johannes and Cori Daines and Thomas Keens and Herschel Scher and Subramanyam Chittivelu and Sudhakar Reddivalam and Klingsberg, {Ross Carl} and Johnson, {Larry G.} and Stijn Verhulst",

note = "Funding Information: In this phase 3 trial in people with cystic fibrosis homozygous for the F508del mutation, in which all participants had a 4-week pre-treatment period with tezacaftor plus ivacaftor, treatment with the triple combination regimen of elexacaftor plus tezacaftor plus ivacaftor resulted in substantial improvements in lung function, sweat chloride concentration, respiratory-related quality of life, and nutritional parameters compared with tezacaftor plus ivacaftor alone. Similar results were observed across all subgroups. Elexacaftor plus tezacaftor plus ivacaftor was well tolerated, with a safety profile comparable to that in the group receiving tezacaftor plus ivacaftor alone. The most commonly reported adverse events were consistent with typical manifestations of cystic fibrosis. To date, clinical results following treatment with ivacaftor in people with cystic fibrosis with the G551D mutation are considered to be the benchmark for treatment with highly effective CFTR modulators. Following 24 weeks of ivacaftor therapy, the increase in ppFEV 1 of 10·6 percentage points and a substantial reduction in pulmonary exacerbations compared with placebo 7 were sustained in a 96-week trial. 21 Ivacaftor therapy has also been shown to be associated with a decreased need for lung transplant and improved survival with long-term use. 22,23 Comparatively, people with cystic fibrosis homozygous for F508del treated with tezacaftor plus ivacaftor had an increase in ppFEV 1 of 4 percentage points compared with placebo. 12 The 10·0-percentage-point improvement in lung function with elexacaftor plus tezacaftor plus ivacaftor compared with tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del observed in the current trial is similar to that seen with ivacaftor in people with cystic fibrosis and the G551D mutation. 7 Data from the 96-week open-label study of the triple combination regimen in people with cystic fibrosis who are homozygous or heterozygous for F508del ( ClinicalTrials.gov , NCT03525574 ) will be obtained to confirm the sustainability of these outcomes over a longer period of time. To understand how the effects of the triple combination regimen in people with cystic fibrosis homozygous for the F508del mutation would have compared if a placebo control, rather than an active control, had been used, the improvements in clinical outcomes and CFTR function previously reported in this population for tezacaftor plus ivacaftor over placebo should be considered. In the current trial, participants started the triple combination regimen after a run-in with tezacaftor plus ivacaftor. The treatment effect of tezacaftor plus ivacaftor is reflected in the baseline sweat chloride concentration of 90 mmol/L, which is comparable to that observed at the end of the tezacaftor plus ivacaftor versus placebo trial, 12 and approximately 10 mmol/L below that in untreated people with cystic fibrosis homozygous for F508del . The addition of elexacaftor to tezacaftor plus ivacaftor in this trial resulted in a mean sweat chloride concentration of 48·0 mmol/L at week 4, which is below the diagnostic threshold for cystic fibrosis (60 mmol/L). 18 Likewise, the improvements in lung function (10 percentage points in ppFEV 1 ) observed with elexacaftor plus tezacaftor plus ivacaftor compared with tezacaftor plus ivacaftor in the present trial might be taken into context with the demonstrated impact of tezacaftor plus ivacaftor in this population (a 4-percentage-point improvement in ppFEV 1 compared with placebo). 12 It is useful to frame these results observed in trial participants taking elexacaftor plus tezacaftor plus ivacaftor, and the magnitude of CFTR modulation they represent, in the context of the overall degree of CFTR modulation and the clinical benefits observed in people with cystic fibrosis and a G551D mutation treated with ivacaftor. 7 Benefits of the triple combination regimen were also observed for other important outcomes, including surrogates for nutritional health. Although the treatment duration in this trial was only 4 weeks, an increase in BMI and bodyweight was observed in the elexacaftor plus tezacaftor plus ivacaftor group compared with participants who received tezacaftor plus ivacaftor alone. Improvements in bodyweight and BMI were not observed in a 24-week study of tezacaftor plus ivacaftor in the same population. 12 Weight and BMI in people with cystic fibrosis are closely correlated with improvements in lung function and are independent predictors of survival. 24,25 The improvements in weight and BMI over 4 weeks observed herein are therefore promising. Pulmonary exacerbations are important life events for people with cystic fibrosis and are associated with a greater rate of lung function decline and decreased survival. 24,26 Although not defined as an efficacy outcome in this 4-week trial, there was a reduction in reported adverse events of infective pulmonary exacerbation of cystic fibrosis in the elexacaftor plus tezacaftor plus ivacaftor group compared with the tezacaftor plus ivacaftor group. These results and those observed in the longer companion trial in people with cystic fibrosis heterozygous for the F508del mutation, in which treatment with elexacaftor plus tezacaftor plus ivacaftor resulted in a 63% reduction in pulmonary exacerbations compared with placebo, 27 provide encouraging evidence of the effect of this triple combination regimen on pulmonary exacerbations compared with the current standard of care. Most phase 3 trials assessing the efficacy of CFTR modulators have used treatment periods of 24 weeks or longer, and a potential limitation of this trial is the 4-week duration. 7,11,12 However, a 4-week duration was selected for this trial on the basis of observations that short-term changes in lung function have consistently been shown within 4 weeks of treatment with CFTR modulators in previous randomised controlled trials, and that these short-term improvements in lung function have been sustained through 24 weeks of treatment. 7,11,12 The 4-week duration of this trial is also based on the premise that the safety profile observed in the concurrent 24-week trial of elexacaftor plus tezacaftor plus ivacaftor in people with cystic fibrosis heterozygous for F508del 27 would be applicable to people with cystic fibrosis homozygous for F508del . The second assumption is supported by previous data with CFTR modulators showing comparable safety data across numerous cystic fibrosis genotypes. 7,8,28 Long-term outcomes of elexacaftor plus tezacaftor plus ivacaftor will be evaluated in ongoing investigations, including the open-label extension of this trial and post-approval observational studies. In conclusion, the results of this phase 3 trial demonstrate the efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor in participants homozygous for F508del over a 4-week study period. In the concurrent phase 3 trial in people with cystic fibrosis in whom a single F508del mutation was responsible for the treatment response, marked improvements in clinical outcomes substantiate the ability of the triple combination regimen to restore F508del-CFTR function. 27 Based on the known impact of the benchmark therapy ivacaftor in a small subset of people with cystic fibrosis, the introduction of elexacaftor plus tezacaftor plus ivacaftor is expected to lead to meaningful improvements in the lives of people with cystic fibrosis homozygous for F508del . This degree of CFTR modulation in such a large proportion of people with cystic fibrosis could profoundly affect the face of cystic fibrosis care. Contributors The VX17-445-103 study was designed by the study sponsor, Vertex Pharmaceuticals, in collaboration with EFM, SMR, ET, MAM, BWR, and JLT-C. HGMH, DGD, EVB, JJW, JLT-C, and KSM enrolled participants and collected the data, which were analysed by the sponsor. All authors participated in the analysis and interpretation of study data, drafting and critically revising the manuscript for important intellectual content, and gave final approval of the manuscript for publication. Declaration of interests 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 (Charit{\'e}-Universit{\"a}tsmedizin 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: Vertex Pharmaceuticals is committed to advancing medical science and improving patient health. This commitment includes the responsible sharing of clinical trial data with qualified researchers. Proposals for the use of these data will be reviewed by a scientific board. Approvals are at the discretion of Vertex Pharmaceuticals and will be dependent on the nature of the request, the merit of the research proposed, and the intended use of the data. Please contact CTDS@vrtx.com if you would like to submit a proposal or need more information. Acknowledgments 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. ",

year = "2019",

month = nov,

day = "23",

doi = "10.1016/S0140-6736(19)32597-8",

language = "English (US)",

volume = "394",

pages = "1940--1948",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier Limited",

number = "10212",

}

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 - VX17-445-103 Trial Group

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.

AU - McCoy, Karen

AU - Donaldson, Scott

AU - Walker, Seth

AU - Chmiel, James

AU - Rubenstein, Ronald

AU - Froh, Deborah K.

AU - Neuringer, Isabel

AU - Jain, Manu

AU - Moffett, Kathryn

AU - Taylor-Cousar, Jennifer L.

AU - Barnett, Bruce

AU - Mueller, Gary

AU - Flume, Patrick

AU - Livingston, Floyd

AU - Mehdi, Nighat

AU - Teneback, Charlotte

AU - Welter, John

AU - Jain, Raksha

AU - Kissner, Dana

AU - Patel, Kapilkumar

AU - Calimano, Francisco J.

AU - Johannes, Jimmy

AU - Daines, Cori

AU - Keens, Thomas

AU - Scher, Herschel

AU - Chittivelu, Subramanyam

AU - Reddivalam, Sudhakar

AU - Klingsberg, Ross Carl

AU - Johnson, Larry G.

AU - Verhulst, Stijn

N1 - Funding Information: In this phase 3 trial in people with cystic fibrosis homozygous for the F508del mutation, in which all participants had a 4-week pre-treatment period with tezacaftor plus ivacaftor, treatment with the triple combination regimen of elexacaftor plus tezacaftor plus ivacaftor resulted in substantial improvements in lung function, sweat chloride concentration, respiratory-related quality of life, and nutritional parameters compared with tezacaftor plus ivacaftor alone. Similar results were observed across all subgroups. Elexacaftor plus tezacaftor plus ivacaftor was well tolerated, with a safety profile comparable to that in the group receiving tezacaftor plus ivacaftor alone. The most commonly reported adverse events were consistent with typical manifestations of cystic fibrosis. To date, clinical results following treatment with ivacaftor in people with cystic fibrosis with the G551D mutation are considered to be the benchmark for treatment with highly effective CFTR modulators. Following 24 weeks of ivacaftor therapy, the increase in ppFEV 1 of 10·6 percentage points and a substantial reduction in pulmonary exacerbations compared with placebo 7 were sustained in a 96-week trial. 21 Ivacaftor therapy has also been shown to be associated with a decreased need for lung transplant and improved survival with long-term use. 22,23 Comparatively, people with cystic fibrosis homozygous for F508del treated with tezacaftor plus ivacaftor had an increase in ppFEV 1 of 4 percentage points compared with placebo. 12 The 10·0-percentage-point improvement in lung function with elexacaftor plus tezacaftor plus ivacaftor compared with tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del observed in the current trial is similar to that seen with ivacaftor in people with cystic fibrosis and the G551D mutation. 7 Data from the 96-week open-label study of the triple combination regimen in people with cystic fibrosis who are homozygous or heterozygous for F508del ( ClinicalTrials.gov , NCT03525574 ) will be obtained to confirm the sustainability of these outcomes over a longer period of time. To understand how the effects of the triple combination regimen in people with cystic fibrosis homozygous for the F508del mutation would have compared if a placebo control, rather than an active control, had been used, the improvements in clinical outcomes and CFTR function previously reported in this population for tezacaftor plus ivacaftor over placebo should be considered. In the current trial, participants started the triple combination regimen after a run-in with tezacaftor plus ivacaftor. The treatment effect of tezacaftor plus ivacaftor is reflected in the baseline sweat chloride concentration of 90 mmol/L, which is comparable to that observed at the end of the tezacaftor plus ivacaftor versus placebo trial, 12 and approximately 10 mmol/L below that in untreated people with cystic fibrosis homozygous for F508del . The addition of elexacaftor to tezacaftor plus ivacaftor in this trial resulted in a mean sweat chloride concentration of 48·0 mmol/L at week 4, which is below the diagnostic threshold for cystic fibrosis (60 mmol/L). 18 Likewise, the improvements in lung function (10 percentage points in ppFEV 1 ) observed with elexacaftor plus tezacaftor plus ivacaftor compared with tezacaftor plus ivacaftor in the present trial might be taken into context with the demonstrated impact of tezacaftor plus ivacaftor in this population (a 4-percentage-point improvement in ppFEV 1 compared with placebo). 12 It is useful to frame these results observed in trial participants taking elexacaftor plus tezacaftor plus ivacaftor, and the magnitude of CFTR modulation they represent, in the context of the overall degree of CFTR modulation and the clinical benefits observed in people with cystic fibrosis and a G551D mutation treated with ivacaftor. 7 Benefits of the triple combination regimen were also observed for other important outcomes, including surrogates for nutritional health. Although the treatment duration in this trial was only 4 weeks, an increase in BMI and bodyweight was observed in the elexacaftor plus tezacaftor plus ivacaftor group compared with participants who received tezacaftor plus ivacaftor alone. Improvements in bodyweight and BMI were not observed in a 24-week study of tezacaftor plus ivacaftor in the same population. 12 Weight and BMI in people with cystic fibrosis are closely correlated with improvements in lung function and are independent predictors of survival. 24,25 The improvements in weight and BMI over 4 weeks observed herein are therefore promising. Pulmonary exacerbations are important life events for people with cystic fibrosis and are associated with a greater rate of lung function decline and decreased survival. 24,26 Although not defined as an efficacy outcome in this 4-week trial, there was a reduction in reported adverse events of infective pulmonary exacerbation of cystic fibrosis in the elexacaftor plus tezacaftor plus ivacaftor group compared with the tezacaftor plus ivacaftor group. These results and those observed in the longer companion trial in people with cystic fibrosis heterozygous for the F508del mutation, in which treatment with elexacaftor plus tezacaftor plus ivacaftor resulted in a 63% reduction in pulmonary exacerbations compared with placebo, 27 provide encouraging evidence of the effect of this triple combination regimen on pulmonary exacerbations compared with the current standard of care. Most phase 3 trials assessing the efficacy of CFTR modulators have used treatment periods of 24 weeks or longer, and a potential limitation of this trial is the 4-week duration. 7,11,12 However, a 4-week duration was selected for this trial on the basis of observations that short-term changes in lung function have consistently been shown within 4 weeks of treatment with CFTR modulators in previous randomised controlled trials, and that these short-term improvements in lung function have been sustained through 24 weeks of treatment. 7,11,12 The 4-week duration of this trial is also based on the premise that the safety profile observed in the concurrent 24-week trial of elexacaftor plus tezacaftor plus ivacaftor in people with cystic fibrosis heterozygous for F508del 27 would be applicable to people with cystic fibrosis homozygous for F508del . The second assumption is supported by previous data with CFTR modulators showing comparable safety data across numerous cystic fibrosis genotypes. 7,8,28 Long-term outcomes of elexacaftor plus tezacaftor plus ivacaftor will be evaluated in ongoing investigations, including the open-label extension of this trial and post-approval observational studies. In conclusion, the results of this phase 3 trial demonstrate the efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor in participants homozygous for F508del over a 4-week study period. In the concurrent phase 3 trial in people with cystic fibrosis in whom a single F508del mutation was responsible for the treatment response, marked improvements in clinical outcomes substantiate the ability of the triple combination regimen to restore F508del-CFTR function. 27 Based on the known impact of the benchmark therapy ivacaftor in a small subset of people with cystic fibrosis, the introduction of elexacaftor plus tezacaftor plus ivacaftor is expected to lead to meaningful improvements in the lives of people with cystic fibrosis homozygous for F508del . This degree of CFTR modulation in such a large proportion of people with cystic fibrosis could profoundly affect the face of cystic fibrosis care. Contributors The VX17-445-103 study was designed by the study sponsor, Vertex Pharmaceuticals, in collaboration with EFM, SMR, ET, MAM, BWR, and JLT-C. HGMH, DGD, EVB, JJW, JLT-C, and KSM enrolled participants and collected the data, which were analysed by the sponsor. All authors participated in the analysis and interpretation of study data, drafting and critically revising the manuscript for important intellectual content, and gave final approval of the manuscript for publication. Declaration of interests 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: Vertex Pharmaceuticals is committed to advancing medical science and improving patient health. This commitment includes the responsible sharing of clinical trial data with qualified researchers. Proposals for the use of these data will be reviewed by a scientific board. Approvals are at the discretion of Vertex Pharmaceuticals and will be dependent on the nature of the request, the merit of the research proposed, and the intended use of the data. Please contact CTDS@vrtx.com if you would like to submit a proposal or need more information. Acknowledgments 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.

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 (ppFEV1) 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 ppFEV1 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 ppFEV1 (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 (ppFEV1) 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 ppFEV1 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 ppFEV1 (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.

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U2 - 10.1016/S0140-6736(19)32597-8

DO - 10.1016/S0140-6736(19)32597-8

M3 - Article

C2 - 31679946

AN - SCOPUS:85074786708

VL - 394

SP - 1940

EP - 1948

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10212

ER -