Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 373, Issue 3, Pages 220-231Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1409547
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Funding
- Vertex Pharmaceuticals
- Children's Hospital Foundation, Brisbane, Queensland, Australia
- Northern Ireland Clinical Research Network (Respiratory Health) in Belfast Health and Social Care Trust
- Institute of Translational Health Sciences, National Institutes of Health (NIH) [UL1TR000423]
- Cystic Fibrosis Translational Research Center, NIH [P30DK089507]
- National Institute for Health Research Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London
- South Carolina Clinical and Translational Research Institute, Medical University of South Carolina [UL1TR000062]
- Clinical and Translational Science Collaborative of Cleveland [UL1TR000439]
- Cystic Fibrosis Core Center [DK027651]
- Cystic Fibrosis Foundation Therapeutics Development Network to Case Western Reserve University School of Medicine
- Northwestern University Clinical and Translational Sciences Institute [UL1RR025741]
- Cystic Fibrosis Foundation Therapeutics Development Network [MCCOLL14YO]
- UAB Center for Clinical and Translational Science [UL1TR000165]
- UAB Cystic Fibrosis Research Center [DK072482]
- Cystic Fibrosis Foundation
- Johns Hopkins Institute for Clinical and Translational Research - NIH [UL1TR001079]
- Medscape
- Vertex
- Novartis
- GlaxoSmithKline
- Novo Nordisk
- Boehringer Ingelheim
- Achaogen
- Apartia
- Bayer Healthcare
- Breathe Easy
- Bristol-Myers Squibb
- Catabasis
- 12th Man Technologies
- Caltaxsys
- Corbus Pharmaceuticals
- Cornerstone Therapeutics
- CSL Behring
- CURx Pharmaceuticals
- Eli Lilly
- Flatley Discovery Lab
- Genentech
- Gilead Sciences
- GlycoMimetics
- Grifols Therapeutics
- INC Research
- Insmed
- KaloBios
- Kamada
- Mpex Pharmaceuticals
- N30 Pharmaceuticals
- Nordmark
- Parion Sciences
- PharmagenesisPharmagenesis (Cornerstone 281)
- Pharmaxis
- ProQR Therapeutics
- Pulmatrix
- PulmoFlow
- Respira Therapeutics
- Savara Pharmaceuticals
- Proteostasis
- Gilead
- Ablynx
- Galapagos
- PTC Therapeutics
- Celtaxys
- Digestive Care
- Chiesi
- Celtaxsys
- AbbVie
- Janssen
- N30 Pharmceuticals
- Bayer
- Talecris
- Roche
- Forest Research Institute
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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 (FEV 1) at week 24. RESULTS A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV 1 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 FEV 1 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.
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