Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR
Claire E Wainwright, J Stuart Elborn, Bonnie W Ramsey, Gautham Marigowda, Xiaohong Huang, Marco Cipolli, Carla Colombo, Jane C Davies, Kris De Boeck, Patrick A Flume, Michael W Konstan, Susanna A McColley, Karen McCoy, Edward F McKone, Anne Munck, Felix Ratjen, Steven M Rowe, David Waltz, Michael P Boyle, TRAFFIC Study Group, TRANSPORT Study Group, 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, Claire E Wainwright, J Stuart Elborn, Bonnie W Ramsey, Gautham Marigowda, Xiaohong Huang, Marco Cipolli, Carla Colombo, Jane C Davies, Kris De Boeck, Patrick A Flume, Michael W Konstan, Susanna A McColley, Karen McCoy, Edward F McKone, Anne Munck, Felix Ratjen, Steven M Rowe, David Waltz, Michael P Boyle, TRAFFIC Study Group, TRANSPORT Study Group, 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
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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Source: PubMed