Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR

doi:10.1056/NEJMoa1409547

Clinical Trial

. 2015 Jul 16;373(3):220-31.

doi: 10.1056/NEJMoa1409547. Epub 2015 May 17.

Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR

Collaborators, Affiliations

Collaborators

Ronald Gibson, Steven Rowe, Michael Boyle, John Clancy, Scott Donaldson, Richard Moss, Seth Walker, Michael Powers, Hugo Escobar, Maria Berdella, Deborah Froh, Robert Vender, Mary Fracchia, Susanna McColley, Kathryn Moffett, Samya Nasr, Jennifer Taylor-Cousar, John Rogers, Gregory Shay, Perry Brown, Henry Dorkin, Robert Zanni, Robert Fink, Gregory Omlor, Keith Meyer, Edward Naureckas, H Worth, Dion Roberts, Laurie Whittaker-LeClair, Allen Dozor, Adupa Rao, Mark Rolfe, Rodolfo Amaro-Galvez, Ariel Berlinski, Francisco Calimano, Terry Chin, Douglas Conrad, Cori Daines, Cynthia Epstein, Deanna Green, Mariam Ischander, Thomas Keens, Jorge Lascano, Juan Martinez, Bennie McWilliams, Anthony Sauder, Arvey Stone, Reddivalam Sudhakar, Mark Weatherly, Bruce Ludwig, Felix Ratjen, Elizabeth Tullis, Mark Chilvers, Roger Michael, Shawn Aaron, Helge Hebestreit, Theodor Zimmermann, Pavel Drevinek, Doris Staab, Radka Bittenglova, Lukas Homola, Joachim Riethmueller, Silke van Koningsbrugge, Hubert Wirtz, Damian Doney, Mary Carroll, Edward Nash, Nicholas Withers, Alan Smyth, Gilles Rault, Dominique Hubert, Isabelle Sermet-Gaudelus, Marleen Bakker, Philippe Reix, Isabelle Durieu, Laurence Weiss, Harry Heijerman, Peter Merkus, Els Weersink, Paul McNally, Edward McKone, Peter Greally, Hiranjan Selvadurai, Hugh Greville, Peter Middleton, Peter Wark, Cesare Braggion, Marco Cipolli, Carla Colombo, Rolando Gagliardini, Vincenzina Lucidi, Laura Minicucci, Serena Quattrucci, Lena Hjelte, Annika Hollsing, Marita Gilljam, Richard Ahrens, Karen McCoy, Moira Aitken, Michael Konstan, Joesph Pilewski, Joanne Billings, Ronald Rubenstein, Albert Faro, Ran Anbar, Carla Frederick, Theodore Liou, John Colombo, Gregory Montgomery, Michael Anstead, Susan Millard, Alison Miller, Tara Barto, Julie Biller, Pierre Vauthy, Jonathan Zuckerman, Jonathan Rosen, Karen Schultz, Emily DiMango, Stanley Fiel, Patrick Flume, Clement Ren, James Royall, Matthias Salathe, Howard Schmidt, Craig Lapin, Dennis Stokes, Mark Dovey, Brian O'Sullivan, Frank Accurso, Carolyn Cannon, Michael McCarthy, Dana Kissner, John McNamara, Hengameh Heidarian-Raissy, Marie Egan, Karen Hardy, Jeffrey Hoag, Joseph Marc Majure, Joel Mermis, Brian Morrissey, Santiago Reyes De La Rocha, Thomas Scanlin, David Schaeffer, Pedro Sepulveda, James Wallace, Jamie Wooldridge, Pearce Wilcox, Larry Lands, Harvey Rabin, Neil Brown, Burkhard Tuemmler, Matthias Griese, Jochen Mainz, Manfred Ballmann, Wolfgang Gleiber, Tacjana Pressler, Rudolf Huber, Lutz Naehrlich, Rainald Fischer, Jane Davies, Simon Doe, Tom Hilliard, Daniel Pecham, Martin Walshaw, Timothy Lee, Anne Munck, Kris De Boeck, Raphael Chiron, Hedwige Bobolie, Frans De Baets, Christiane Knoop, Francois Bremont, Michael Fayon, Martine Reynaud-Gaubert, Nathalie Wizla, Silvia Gartner, Amparo Sole Jover, Javier de Gracia Roldan, David Serisier, Claire Wainwright, Scott Bell, Philip Thompson, Barry Clements, Helmut Ellemunter, Helmut Feizelmeier

Affiliation

¹ From Queensland Children's Medical Research Institute, Royal Children's Hospital, Lady Cilento Children's Hospital, and University of Queensland School of Medicine, Brisbane, Australia (C.E.W.); Queens University of Belfast, Belfast (J.S.E.), and Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London (J.C.D.) - all in the United Kingdom; Seattle Children's Hospital and University of Washington School of Medicine, Seattle (B.W.R.); Vertex Pharmaceuticals, Boston (G.M., X.H., D.W.); Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, Verona (M.C.), and Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, Milan (C.C.) - both in Italy; University Hospital Gasthuisberg, Leuven, Belgium (K.D.B.); Medical University of South Carolina, Charleston (P.A.F.); Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland (M.W.K.), and the Department of Pediatrics, Pulmonary Division, Nationwide Children's Hospital and Ohio State University, Columbus (K.M.) - both in Ohio; Stanley Manne Children's Research Institute, Northwestern University Feinberg School of Medicine, Chicago (S.A.M.); St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin (E.F.M.); Hôpital Robert Debré, Paediatric Gastroenterology and Respiratory Department, CF Center, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris (A.M.); Division of Respiratory Medicine, Department of Pediatrics, Physiology, and Experimental Medicine, Hospital for Sick Children, University of Toronto, Toronto (F.R.); University of Alabama at Birmingham, Birmingham (S.M.R.); and Johns Hopkins Medicine, Baltimore (M.P.B.).

PMID: 25981758
PMCID: PMC4764353
DOI: 10.1056/NEJMoa1409547

Clinical Trial

Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR

Claire E Wainwright et al. N Engl J Med. 2015.

. 2015 Jul 16;373(3):220-31.

doi: 10.1056/NEJMoa1409547. Epub 2015 May 17.

Collaborators

Ronald Gibson, Steven Rowe, Michael Boyle, John Clancy, Scott Donaldson, Richard Moss, Seth Walker, Michael Powers, Hugo Escobar, Maria Berdella, Deborah Froh, Robert Vender, Mary Fracchia, Susanna McColley, Kathryn Moffett, Samya Nasr, Jennifer Taylor-Cousar, John Rogers, Gregory Shay, Perry Brown, Henry Dorkin, Robert Zanni, Robert Fink, Gregory Omlor, Keith Meyer, Edward Naureckas, H Worth, Dion Roberts, Laurie Whittaker-LeClair, Allen Dozor, Adupa Rao, Mark Rolfe, Rodolfo Amaro-Galvez, Ariel Berlinski, Francisco Calimano, Terry Chin, Douglas Conrad, Cori Daines, Cynthia Epstein, Deanna Green, Mariam Ischander, Thomas Keens, Jorge Lascano, Juan Martinez, Bennie McWilliams, Anthony Sauder, Arvey Stone, Reddivalam Sudhakar, Mark Weatherly, Bruce Ludwig, Felix Ratjen, Elizabeth Tullis, Mark Chilvers, Roger Michael, Shawn Aaron, Helge Hebestreit, Theodor Zimmermann, Pavel Drevinek, Doris Staab, Radka Bittenglova, Lukas Homola, Joachim Riethmueller, Silke van Koningsbrugge, Hubert Wirtz, Damian Doney, Mary Carroll, Edward Nash, Nicholas Withers, Alan Smyth, Gilles Rault, Dominique Hubert, Isabelle Sermet-Gaudelus, Marleen Bakker, Philippe Reix, Isabelle Durieu, Laurence Weiss, Harry Heijerman, Peter Merkus, Els Weersink, Paul McNally, Edward McKone, Peter Greally, Hiranjan Selvadurai, Hugh Greville, Peter Middleton, Peter Wark, Cesare Braggion, Marco Cipolli, Carla Colombo, Rolando Gagliardini, Vincenzina Lucidi, Laura Minicucci, Serena Quattrucci, Lena Hjelte, Annika Hollsing, Marita Gilljam, Richard Ahrens, Karen McCoy, Moira Aitken, Michael Konstan, Joesph Pilewski, Joanne Billings, Ronald Rubenstein, Albert Faro, Ran Anbar, Carla Frederick, Theodore Liou, John Colombo, Gregory Montgomery, Michael Anstead, Susan Millard, Alison Miller, Tara Barto, Julie Biller, Pierre Vauthy, Jonathan Zuckerman, Jonathan Rosen, Karen Schultz, Emily DiMango, Stanley Fiel, Patrick Flume, Clement Ren, James Royall, Matthias Salathe, Howard Schmidt, Craig Lapin, Dennis Stokes, Mark Dovey, Brian O'Sullivan, Frank Accurso, Carolyn Cannon, Michael McCarthy, Dana Kissner, John McNamara, Hengameh Heidarian-Raissy, Marie Egan, Karen Hardy, Jeffrey Hoag, Joseph Marc Majure, Joel Mermis, Brian Morrissey, Santiago Reyes De La Rocha, Thomas Scanlin, David Schaeffer, Pedro Sepulveda, James Wallace, Jamie Wooldridge, Pearce Wilcox, Larry Lands, Harvey Rabin, Neil Brown, Burkhard Tuemmler, Matthias Griese, Jochen Mainz, Manfred Ballmann, Wolfgang Gleiber, Tacjana Pressler, Rudolf Huber, Lutz Naehrlich, Rainald Fischer, Jane Davies, Simon Doe, Tom Hilliard, Daniel Pecham, Martin Walshaw, Timothy Lee, Anne Munck, Kris De Boeck, Raphael Chiron, Hedwige Bobolie, Frans De Baets, Christiane Knoop, Francois Bremont, Michael Fayon, Martine Reynaud-Gaubert, Nathalie Wizla, Silvia Gartner, Amparo Sole Jover, Javier de Gracia Roldan, David Serisier, Claire Wainwright, Scott Bell, Philip Thompson, Barry Clements, Helmut Ellemunter, Helmut Feizelmeier

Affiliation

¹ From Queensland Children's Medical Research Institute, Royal Children's Hospital, Lady Cilento Children's Hospital, and University of Queensland School of Medicine, Brisbane, Australia (C.E.W.); Queens University of Belfast, Belfast (J.S.E.), and Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London (J.C.D.) - all in the United Kingdom; Seattle Children's Hospital and University of Washington School of Medicine, Seattle (B.W.R.); Vertex Pharmaceuticals, Boston (G.M., X.H., D.W.); Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, Verona (M.C.), and Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, Milan (C.C.) - both in Italy; University Hospital Gasthuisberg, Leuven, Belgium (K.D.B.); Medical University of South Carolina, Charleston (P.A.F.); Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland (M.W.K.), and the Department of Pediatrics, Pulmonary Division, Nationwide Children's Hospital and Ohio State University, Columbus (K.M.) - both in Ohio; Stanley Manne Children's Research Institute, Northwestern University Feinberg School of Medicine, Chicago (S.A.M.); St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin (E.F.M.); Hôpital Robert Debré, Paediatric Gastroenterology and Respiratory Department, CF Center, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris (A.M.); Division of Respiratory Medicine, Department of Pediatrics, Physiology, and Experimental Medicine, Hospital for Sick Children, University of Toronto, Toronto (F.R.); University of Alabama at Birmingham, Birmingham (S.M.R.); and Johns Hopkins Medicine, Baltimore (M.P.B.).

PMID: 25981758
PMCID: PMC4764353
DOI: 10.1056/NEJMoa1409547

Abstract

Background: Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation.

Methods: We conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24.

Results: A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor-ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor-ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor-ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor-ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo.

Conclusions: These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.).

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Figures

**Figure 1. Absolute Changes from Baseline in the Percent-age of Predicted Forced Expiratory Volume in 1 Second (FEV₁) According to Study Group**
The LUM (600 mg/day)–IVA group received 600 mg of lumacaftor (LUM) once daily in combination with 250 mg of ivacaftor (IVA) every 12 hours; the LUM (400 mg every 12 hr)–IVA group received 400 mg of lumacaftor every 12 hours in combination with 250 mg of ivacaftor every 12 hours. Panel A shows the mean absolute change in the percentage of predicted FEV₁ over time in each study group; the difference between each active-treatment group and the placebo group at each time point was significant (P<0.025). Panel B shows subgroup analyses of the differences between the active treatment and placebo in the absolute change from baseline in the percentage of predicted FEV₁ at week 24. Data in both panels are least-squares means; I bars indicate 95% confidence intervals. The results represent pooled data from the TRAFFIC and TRANSPORT studies.

**Figure 2. Pulmonary Exacerbations**
The time to first pulmonary exacerbation and number of pulmonary exacerbations leading to hospitalization or treatment with intravenous antibiotics are shown. In Panel B, the number of pulmonary exacerbations observed through week 24 is expressed as a rate over 48 weeks. The results represent pooled data from the TRAFFIC and TRANSPORT studies.

See this image and copyright information in PMC

Comment in

Another Beginning for Cystic Fibrosis Therapy.
Davis PB. Davis PB. N Engl J Med. 2015 Jul 16;373(3):274-6. doi: 10.1056/NEJMe1504059. Epub 2015 May 17. N Engl J Med. 2015. PMID: 25981385 No abstract available.
A new chapter in therapy for cystic fibrosis.
Bilton D. Bilton D. Lancet Respir Med. 2015 Jul;3(7):e20. doi: 10.1016/S2213-2600(15)00234-9. Epub 2015 Jun 24. Lancet Respir Med. 2015. PMID: 26117158 No abstract available.
Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.
Wainwright CE, Elborn JS, Ramsey BW. Wainwright CE, et al. N Engl J Med. 2015 Oct 29;373(18):1783-4. doi: 10.1056/NEJMc1510466. N Engl J Med. 2015. PMID: 26510034 No abstract available.
Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.
Rehman A, Baloch NU, Janahi IA. Rehman A, et al. N Engl J Med. 2015 Oct 29;373(18):1783. doi: 10.1056/NEJMc1510466. N Engl J Med. 2015. PMID: 26510035 No abstract available.
Clinical Trials of Novel Treatments for Cystic Fibrosis.
Hippolyte S, Pabary R, Waller M, Jones A, Simmonds N, Davies JC. Hippolyte S, et al. Am J Respir Crit Care Med. 2016 Mar 1;193(5):569-71. doi: 10.1164/rccm.201509-1734RR. Am J Respir Crit Care Med. 2016. PMID: 26765316 No abstract available.
[A milestone in cystic fibrosis therapy].
Reinhardt D. Reinhardt D. MMW Fortschr Med. 2015 Nov 5;157(19):34. doi: 10.1007/s15006-015-3723-9. MMW Fortschr Med. 2015. PMID: 26953403 German. No abstract available.

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Gramegna A, Contarini M, Aliberti S, Casciaro R, Blasi F, Castellani C. Gramegna A, et al. Int J Mol Sci. 2020 Aug 16;21(16):5882. doi: 10.3390/ijms21165882. Int J Mol Sci. 2020. PMID: 32824306 Free PMC article.
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Alexander M, Reyfman PA. Alexander M, et al. Am J Respir Cell Mol Biol. 2019 Nov;61(5):558-559. doi: 10.1165/rcmb.2019-0156ED. Am J Respir Cell Mol Biol. 2019. PMID: 31091961 Free PMC article. No abstract available.

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References

1. US CF Foundation, Johns Hopkins University, the Hospital for Sick Children. The clinical and functional translation of CFTR (CFTR2) 2011 ( http://cftr2.org)
1. Cystic Fibrosis Foundation. Patient registry: annual data report, 2012. Bethesda, MD: Cystic Fibrosis Foundation; 2013. ( http://www.cff.org/UploadedFiles/research/ClinicalResearch/PatientRegist...)
1. European Cystic Fibrosis Patient Registry: annual data report, 2010. Denmark: European Cystic Fibrosis Society; 2014. ( https://www.ecfs.eu/files/webfm/webfiles/File/ecfs_registry/ECFSPR_Repor...)
1. The molecular genetic epidemiology of cystic fibrosis: report of a joint meeting of WHO/ECFTN/ICF(M)A/ECFS. Genoa, Italy: World Health Organization; Jun, 2002. p. 24.
1. O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373:1891–904. - PubMed

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[1] US CF Foundation, Johns Hopkins University, the Hospital for Sick Children. The clinical and functional translation of CFTR (CFTR2) 2011 ( http://cftr2.org)

[2] US CF Foundation, Johns Hopkins University, the Hospital for Sick Children. The clinical and functional translation of CFTR (CFTR2) 2011 ( http://cftr2.org)

[3] Cystic Fibrosis Foundation. Patient registry: annual data report, 2012. Bethesda, MD: Cystic Fibrosis Foundation; 2013. ( http://www.cff.org/UploadedFiles/research/ClinicalResearch/PatientRegist...)

[4] Cystic Fibrosis Foundation. Patient registry: annual data report, 2012. Bethesda, MD: Cystic Fibrosis Foundation; 2013. ( http://www.cff.org/UploadedFiles/research/ClinicalResearch/PatientRegist...)

[5] European Cystic Fibrosis Patient Registry: annual data report, 2010. Denmark: European Cystic Fibrosis Society; 2014. ( https://www.ecfs.eu/files/webfm/webfiles/File/ecfs_registry/ECFSPR_Repor...)

[6] European Cystic Fibrosis Patient Registry: annual data report, 2010. Denmark: European Cystic Fibrosis Society; 2014. ( https://www.ecfs.eu/files/webfm/webfiles/File/ecfs_registry/ECFSPR_Repor...)

[7] The molecular genetic epidemiology of cystic fibrosis: report of a joint meeting of WHO/ECFTN/ICF(M)A/ECFS. Genoa, Italy: World Health Organization; Jun, 2002. p. 24.

[8] The molecular genetic epidemiology of cystic fibrosis: report of a joint meeting of WHO/ECFTN/ICF(M)A/ECFS. Genoa, Italy: World Health Organization; Jun, 2002. p. 24.

[9] O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373:1891–904. - PubMed

[10] O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373:1891–904. - PubMed

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Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR

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Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR

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